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  • Protein Binding  (130)
  • Crystallography, X-Ray  (123)
  • Nature Publishing Group (NPG)  (221)
  • Essen : Verl. Glückauf
  • Krefeld : Geologischer Dienst Nordhein-Westfalen
  • Springer Nature
  • 2005-2009  (221)
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  • 1
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    Crystal structure of DNA-PKcs reveals a large open-ring cradle comprised of HEAT repeats (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-12-22
    Description: Broken chromosomes arising from DNA double-strand breaks result from endogenous events such as the production of reactive oxygen species during cellular metabolism, as well as from exogenous sources such as ionizing radiation. Left unrepaired or incorrectly repaired they can lead to genomic changes that may result in cell death or cancer. DNA-dependent protein kinase (DNA-PK), a holoenzyme that comprises the DNA-PK catalytic subunit (DNA-PKcs) and the heterodimer Ku70/Ku80, has a major role in non-homologous end joining-the main pathway in mammals used to repair double-strand breaks. DNA-PKcs is a serine/threonine protein kinase comprising a single polypeptide chain of 4,128 amino acids and belonging to the phosphatidylinositol-3-OH kinase (PI(3)K)-related protein family. DNA-PKcs is involved in the sensing and transmission of DNA damage signals to proteins such as p53, setting off events that lead to cell cycle arrest. It phosphorylates a wide range of substrates in vitro, including Ku70/Ku80, which is translocated along DNA. Here we present the crystal structure of human DNA-PKcs at 6.6 A resolution, in which the overall fold is clearly visible, to our knowledge, for the first time. The many alpha-helical HEAT repeats (helix-turn-helix motifs) facilitate bending and allow the polypeptide chain to fold into a hollow circular structure. The carboxy-terminal kinase domain is located on top of this structure, and a small HEAT repeat domain that probably binds DNA is inside. The structure provides a flexible cradle to promote DNA double-strand-break repair.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2811870/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2811870/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sibanda, Bancinyane L -- Chirgadze, Dimitri Y -- Blundell, Tom L -- 079281/Wellcome Trust/United Kingdom -- A3846/Cancer Research UK/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2010 Jan 7;463(7277):118-21. doi: 10.1038/nature08648. Epub 2009 Dec 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Cambridge, Old Addenbrooke's site, 80 Tennis Court Road, Cambridge CB2 1GA, UK. lynn@cryst.bioc.cam.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20023628" target="_blank"〉PubMed〈/a〉
    Keywords: Antigens, Nuclear/chemistry ; Catalytic Domain ; Crystallography, X-Ray ; DNA/metabolism ; DNA Breaks, Double-Stranded ; DNA-Activated Protein Kinase/*chemistry/metabolism ; DNA-Binding Proteins/chemistry ; HeLa Cells ; *Helix-Turn-Helix Motifs ; Humans ; Models, Molecular ; Nuclear Proteins/*chemistry/metabolism ; Protein Folding ; Protein Structure, Secondary
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
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    A structural explanation for the binding of endocytic dileucine motifs by the AP2 complex (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-01-14
    Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340503/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340503/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kelly, Bernard T -- McCoy, Airlie J -- Spate, Kira -- Miller, Sharon E -- Evans, Philip R -- Honing, Stefan -- Owen, David J -- 090909/Wellcome Trust/United Kingdom -- MC_U105178845/Medical Research Council/United Kingdom -- England -- Nature. 2008 Dec 18;456(7224):976-79. doi: 10.1038/nature07422.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19140243" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Protein Complex 2/*chemistry/genetics/*metabolism ; Amino Acid Motifs ; Animals ; Antigens, CD4/*chemistry/*metabolism ; Binding Sites ; Conserved Sequence ; *Endocytosis ; Humans ; Leucine/*metabolism ; Mice ; Models, Molecular ; Protein Binding ; Protein Conformation ; Protein Subunits/chemistry/genetics/metabolism ; Rats
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    Cancer-associated IDH1 mutations produce 2-hydroxyglutarate (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-11-26
    Description: Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a common feature of a major subset of primary human brain cancers. These mutations occur at a single amino acid residue of the IDH1 active site, resulting in loss of the enzyme's ability to catalyse conversion of isocitrate to alpha-ketoglutarate. However, only a single copy of the gene is mutated in tumours, raising the possibility that the mutations do not result in a simple loss of function. Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of alpha-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). Structural studies demonstrate that when arginine 132 is mutated to histidine, residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert alpha-ketoglutarate to 2HG. Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumours in patients with inborn errors of 2HG metabolism. Similarly, in human malignant gliomas harbouring IDH1 mutations, we find markedly elevated levels of 2HG. These data demonstrate that the IDH1 mutations result in production of the onco-metabolite 2HG, and indicate that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2818760/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2818760/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dang, Lenny -- White, David W -- Gross, Stefan -- Bennett, Bryson D -- Bittinger, Mark A -- Driggers, Edward M -- Fantin, Valeria R -- Jang, Hyun Gyung -- Jin, Shengfang -- Keenan, Marie C -- Marks, Kevin M -- Prins, Robert M -- Ward, Patrick S -- Yen, Katharine E -- Liau, Linda M -- Rabinowitz, Joshua D -- Cantley, Lewis C -- Thompson, Craig B -- Vander Heiden, Matthew G -- Su, Shinsan M -- P01 CA104838/CA/NCI NIH HHS/ -- P01 CA104838-05/CA/NCI NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 CA105463/CA/NCI NIH HHS/ -- R01 CA105463-06/CA/NCI NIH HHS/ -- R21 CA128620/CA/NCI NIH HHS/ -- England -- Nature. 2009 Dec 10;462(7274):739-44. doi: 10.1038/nature08617. Epub .〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19935646" target="_blank"〉PubMed〈/a〉
    Keywords: Arginine/genetics ; Brain Neoplasms/*genetics/*metabolism/pathology ; Catalytic Domain ; Cell Line ; Crystallography, X-Ray ; Disease Progression ; Enzyme Assays ; Glioma/genetics/metabolism/pathology ; Glutarates/*metabolism ; Histidine/genetics/metabolism ; Humans ; Isocitrate Dehydrogenase/*genetics/*metabolism ; Ketoglutaric Acids/metabolism ; Models, Molecular ; Mutant Proteins/*genetics/*metabolism ; Mutation/genetics ; Protein Conformation
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    Malaria: The gatekeeper revealed (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-06-19
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reiff, Sarah B -- Striepen, Boris -- England -- Nature. 2009 Jun 18;459(7249):918-9. doi: 10.1038/459918a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19536248" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Humans ; Malaria, Falciparum/drug therapy/*parasitology ; Models, Biological ; Plasmodium falciparum/*metabolism ; Protein Binding ; Protein Transport ; Protozoan Proteins/antagonists & inhibitors/*metabolism ; Vacuoles/metabolism/parasitology
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    Crystal structure of the ATP-gated P2X(4) ion channel in the closed state (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-07-31
    Description: P2X receptors are cation-selective ion channels gated by extracellular ATP, and are implicated in diverse physiological processes, from synaptic transmission to inflammation to the sensing of taste and pain. Because P2X receptors are not related to other ion channel proteins of known structure, there is at present no molecular foundation for mechanisms of ligand-gating, allosteric modulation and ion permeation. Here we present crystal structures of the zebrafish P2X(4) receptor in its closed, resting state. The chalice-shaped, trimeric receptor is knit together by subunit-subunit contacts implicated in ion channel gating and receptor assembly. Extracellular domains, rich in beta-strands, have large acidic patches that may attract cations, through fenestrations, to vestibules near the ion channel. In the transmembrane pore, the 'gate' is defined by an approximately 8 A slab of protein. We define the location of three non-canonical, intersubunit ATP-binding sites, and suggest that ATP binding promotes subunit rearrangement and ion channel opening.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720809/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720809/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kawate, Toshimitsu -- Michel, Jennifer Carlisle -- Birdsong, William T -- Gouaux, Eric -- U54 GM075026/GM/NIGMS NIH HHS/ -- U54 GM075026-04/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Jul 30;460(7255):592-8. doi: 10.1038/nature08198.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vollum Institute, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Oregon 97239, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19641588" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Animals ; Binding Sites ; Cell Line ; Crystallography, X-Ray ; Gadolinium/metabolism ; Humans ; Ion Channels/antagonists & inhibitors/*chemistry ; Membrane Proteins/chemistry ; *Models, Molecular ; Protein Binding ; Protein Folding ; Protein Structure, Tertiary ; Purinergic P2 Receptor Antagonists ; Receptors, Purinergic P2/*chemistry ; Receptors, Purinergic P2X4 ; Zebrafish/*physiology ; Zebrafish Proteins/antagonists & inhibitors/*chemistry
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  • 6
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    Riboflavin kinase couples TNF receptor 1 to NADPH oxidase (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-07-31
    Description: Reactive oxygen species (ROS) produced by NADPH oxidase function as defence and signalling molecules related to innate immunity and various cellular responses. The activation of NADPH oxidase in response to plasma membrane receptor activation depends on the phosphorylation of cytoplasmic oxidase subunits, their translocation to membranes and the assembly of all NADPH oxidase components. Tumour necrosis factor (TNF) is a prominent stimulus of ROS production, but the molecular mechanisms by which TNF activates NADPH oxidase are poorly understood. Here we identify riboflavin kinase (RFK, formerly known as flavokinase) as a previously unrecognized TNF-receptor-1 (TNFR1)-binding protein that physically and functionally couples TNFR1 to NADPH oxidase. In mouse and human cells, RFK binds to both the TNFR1-death domain and to p22(phox), the common subunit of NADPH oxidase isoforms. RFK-mediated bridging of TNFR1 and p22(phox) is a prerequisite for TNF-induced but not for Toll-like-receptor-induced ROS production. Exogenous flavin mononucleotide or FAD was able to substitute fully for TNF stimulation of NADPH oxidase in RFK-deficient cells. RFK is rate-limiting in the synthesis of FAD, an essential prosthetic group of NADPH oxidase. The results suggest that TNF, through the activation of RFK, enhances the incorporation of FAD in NADPH oxidase enzymes, a critical step for the assembly and activation of NADPH oxidase.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yazdanpanah, Benjamin -- Wiegmann, Katja -- Tchikov, Vladimir -- Krut, Oleg -- Pongratz, Carola -- Schramm, Michael -- Kleinridders, Andre -- Wunderlich, Thomas -- Kashkar, Hamid -- Utermohlen, Olaf -- Bruning, Jens C -- Schutze, Stefan -- Kronke, Martin -- England -- Nature. 2009 Aug 27;460(7259):1159-63. doi: 10.1038/nature08206. Epub 2009 Jul 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19641494" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cytochrome b Group/metabolism ; Enzyme Activation ; Fibroblasts ; Flavin Mononucleotide/metabolism ; Flavin-Adenine Dinucleotide/biosynthesis/metabolism ; HeLa Cells ; Humans ; Isoenzymes/chemistry/metabolism ; Membrane Glycoproteins/metabolism ; Mice ; NADH, NADPH Oxidoreductases/metabolism ; NADPH Oxidase/chemistry/*metabolism ; Phosphotransferases (Alcohol Group Acceptor)/deficiency/genetics/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Reactive Oxygen Species/metabolism ; Receptors, Tumor Necrosis Factor, Type I/chemistry/*metabolism
    Print ISSN: 0028-0836
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  • 7
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    Molecular basis of transport and regulation in the Na(+)/betaine symporter BetP (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-03-06
    Description: Osmoregulated transporters sense intracellular osmotic pressure and respond to hyperosmotic stress by accumulation of osmolytes to restore normal hydration levels. Here we report the determination of the X-ray structure of a member of the family of betaine/choline/carnitine transporters, the Na(+)-coupled symporter BetP from Corynebacterium glutamicum, which is a highly effective osmoregulated uptake system for glycine betaine. Glycine betaine is bound in a tryptophan box occluded from both sides of the membrane with aromatic side chains lining the transport pathway. BetP has the same overall fold as three unrelated Na(+)-coupled symporters. Whereas these are crystallized in either the outward-facing or the inward-facing conformation, the BetP structure reveals a unique intermediate conformation in the Na(+)-coupled transport cycle. The trimeric architecture of BetP and the break in three-fold symmetry by the osmosensing C-terminal helices suggest a regulatory mechanism of Na(+)-coupled osmolyte transport to counteract osmotic stress.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ressl, Susanne -- Terwisscha van Scheltinga, Anke C -- Vonrhein, Clemens -- Ott, Vera -- Ziegler, Christine -- England -- Nature. 2009 Mar 5;458(7234):47-52. doi: 10.1038/nature07819.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute of Biophysics, Department of Structural Biology, 60438 Frankfurt am Main, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19262666" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/genetics/*metabolism ; Betaine/*metabolism ; Binding Sites ; Carrier Proteins/*chemistry/genetics/*metabolism ; Corynebacterium glutamicum/*chemistry/genetics ; Crystallography, X-Ray ; Ion Transport ; Models, Molecular ; Protein Binding ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Sodium/*metabolism ; Structure-Activity Relationship
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  • 8
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    Signal peptides are allosteric activators of the protein translocase (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-11-20
    Description: Extra-cytoplasmic polypeptides are usually synthesized as 'preproteins' carrying amino-terminal, cleavable signal peptides and secreted across membranes by translocases. The main bacterial translocase comprises the SecYEG protein-conducting channel and the peripheral ATPase motor SecA. Most proteins destined for the periplasm and beyond are exported post-translationally by SecA. Preprotein targeting to SecA is thought to involve signal peptides and chaperones like SecB. Here we show that signal peptides have a new role beyond targeting: they are essential allosteric activators of the translocase. On docking on their binding groove on SecA, signal peptides act in trans to drive three successive states: first, 'triggering' that drives the translocase to a lower activation energy state; second, 'trapping' that engages non-native preprotein mature domains docked with high affinity on the secretion apparatus; and third, 'secretion' during which trapped mature domains undergo several turnovers of translocation in segments. A significant contribution by mature domains renders signal peptides less critical in bacterial secretory protein targeting than currently assumed. Rather, it is their function as allosteric activators of the translocase that renders signal peptides essential for protein secretion. A role for signal peptides and targeting sequences as allosteric activators may be universal in protein translocases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2823582/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2823582/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gouridis, Giorgos -- Karamanou, Spyridoula -- Gelis, Ioannis -- Kalodimos, Charalampos G -- Economou, Anastassios -- GM73854/GM/NIGMS NIH HHS/ -- R01 GM073854/GM/NIGMS NIH HHS/ -- R01 GM073854-03/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Nov 19;462(7271):363-7. doi: 10.1038/nature08559.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology-Hellas, Iraklio, Crete 71110, Greece.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19924216" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/metabolism ; Alkaline Phosphatase/metabolism ; Enzyme Activators/*metabolism ; Escherichia coli/*enzymology ; Escherichia coli Proteins/*metabolism ; Periplasmic Proteins/metabolism ; Protein Binding ; Protein Sorting Signals/*physiology ; Protein Transport
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  • 9
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    Rational design of a structural and functional nitric oxide reductase (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-11-27
    Description: Protein design provides a rigorous test of our knowledge about proteins and allows the creation of novel enzymes for biotechnological applications. Whereas progress has been made in designing proteins that mimic native proteins structurally, it is more difficult to design functional proteins. In comparison to recent successes in designing non-metalloproteins, it is even more challenging to rationally design metalloproteins that reproduce both the structure and function of native metalloenzymes. This is because protein metal-binding sites are much more varied than non-metal-containing sites, in terms of different metal ion oxidation states, preferred geometry and metal ion ligand donor sets. Because of their variability, it has been difficult to predict metal-binding site properties in silico, as many of the parameters, such as force fields, are ill-defined. Therefore, the successful design of a structural and functional metalloprotein would greatly advance the field of protein design and our understanding of enzymes. Here we report a successful, rational design of a structural and functional model of a metalloprotein, nitric oxide reductase (NOR), by introducing three histidines and one glutamate, predicted as ligands in the active site of NOR, into the distal pocket of myoglobin. A crystal structure of the designed protein confirms that the minimized computer model contains a haem/non-haem Fe(B) centre that is remarkably similar to that in the crystal structure. This designed protein also exhibits NO reduction activity, and so models both the structure and function of NOR, offering insight that the active site glutamate is required for both iron binding and activity. These results show that structural and functional metalloproteins can be rationally designed in silico.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297211/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297211/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yeung, Natasha -- Lin, Ying-Wu -- Gao, Yi-Gui -- Zhao, Xuan -- Russell, Brandy S -- Lei, Lanyu -- Miner, Kyle D -- Robinson, Howard -- Lu, Yi -- GM062211/GM/NIGMS NIH HHS/ -- R01 GM062211/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Dec 24;462(7276):1079-82. doi: 10.1038/nature08620. Epub 2009 Nov 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19940850" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Crystallization ; Iron/metabolism ; Models, Molecular ; Myoglobin/chemistry ; Nitric Oxide/metabolism ; Oxidoreductases/*chemical synthesis/*chemistry/metabolism ; Protein Binding ; Protein Structure, Tertiary
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  • 10
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    Transport mechanism of a bacterial homologue of glutamate transporters (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-11-20
    Description: Glutamate transporters are integral membrane proteins that catalyse a thermodynamically uphill uptake of the neurotransmitter glutamate from the synaptic cleft into the cytoplasm of glia and neuronal cells by harnessing the energy of pre-existing electrochemical gradients of ions. Crucial to the reaction is the conformational transition of the transporters between outward and inward facing states, in which the substrate binding sites are accessible from the extracellular space and the cytoplasm, respectively. Here we describe the crystal structure of a double cysteine mutant of a glutamate transporter homologue from Pyrococcus horikoshii, Glt(Ph), which is trapped in the inward facing state by cysteine crosslinking. Together with the previously determined crystal structures of Glt(Ph) in the outward facing state, the structure of the crosslinked mutant allows us to propose a molecular mechanism by which Glt(Ph) and, by analogy, mammalian glutamate transporters mediate sodium-coupled substrate uptake.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2934767/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2934767/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reyes, Nicolas -- Ginter, Christopher -- Boudker, Olga -- R01 NS064357/NS/NINDS NIH HHS/ -- R01 NS064357-01A1/NS/NINDS NIH HHS/ -- England -- Nature. 2009 Dec 17;462(7275):880-5. doi: 10.1038/nature08616. Epub 2009 Nov 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, Box 75, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19924125" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Transport System X-AG/*chemistry/genetics/*metabolism ; Binding Sites ; Biological Transport ; Cross-Linking Reagents ; Crystallography, X-Ray ; Cysteine/genetics/metabolism ; Models, Molecular ; Movement ; Mutant Proteins/chemistry/genetics/metabolism ; Protein Structure, Tertiary ; Pyrococcus horikoshii/*chemistry ; Sodium/metabolism ; Structure-Activity Relationship
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  • 11
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    A gate-latch-lock mechanism for hormone signalling by abscisic acid receptors (2009)
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    Publication Date: 2009-11-10
    Description: Abscisic acid (ABA) is a ubiquitous hormone that regulates plant growth, development and responses to environmental stresses. Its action is mediated by the PYR/PYL/RCAR family of START proteins, but it remains unclear how these receptors bind ABA and, in turn, how hormone binding leads to inhibition of the downstream type 2C protein phosphatase (PP2C) effectors. Here we report crystal structures of apo and ABA-bound receptors as well as a ternary PYL2-ABA-PP2C complex. The apo receptors contain an open ligand-binding pocket flanked by a gate that closes in response to ABA by way of conformational changes in two highly conserved beta-loops that serve as a gate and latch. Moreover, ABA-induced closure of the gate creates a surface that enables the receptor to dock into and competitively inhibit the PP2C active site. A conserved tryptophan in the PP2C inserts directly between the gate and latch, which functions to further lock the receptor in a closed conformation. Together, our results identify a conserved gate-latch-lock mechanism underlying ABA signalling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810868/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810868/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Melcher, Karsten -- Ng, Ley-Moy -- Zhou, X Edward -- Soon, Fen-Fen -- Xu, Yong -- Suino-Powell, Kelly M -- Park, Sang-Youl -- Weiner, Joshua J -- Fujii, Hiroaki -- Chinnusamy, Viswanathan -- Kovach, Amanda -- Li, Jun -- Wang, Yonghong -- Li, Jiayang -- Peterson, Francis C -- Jensen, Davin R -- Yong, Eu-Leong -- Volkman, Brian F -- Cutler, Sean R -- Zhu, Jian-Kang -- Xu, H Eric -- R01 DK066202/DK/NIDDK NIH HHS/ -- R01 DK066202-04/DK/NIDDK NIH HHS/ -- R01 DK071662/DK/NIDDK NIH HHS/ -- R01 DK071662-05/DK/NIDDK NIH HHS/ -- R01 GM087413/GM/NIGMS NIH HHS/ -- R01 GM087413-01/GM/NIGMS NIH HHS/ -- R01 HL089301/HL/NHLBI NIH HHS/ -- R01 HL089301-03/HL/NHLBI NIH HHS/ -- England -- Nature. 2009 Dec 3;462(7273):602-8. doi: 10.1038/nature08613.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, N.E., Grand Rapids, Michigan 49503, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19898420" target="_blank"〉PubMed〈/a〉
    Keywords: Abscisic Acid/*metabolism ; Arabidopsis/genetics/metabolism/*physiology ; Arabidopsis Proteins/*chemistry/genetics/metabolism/*physiology ; Binding Sites ; DNA Mutational Analysis ; *Models, Molecular ; Plants, Genetically Modified ; Protein Binding ; Protein Structure, Tertiary ; Signal Transduction/*physiology
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  • 12
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    JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin (2009)
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    Publication Date: 2009-09-29
    Description: Activation of Janus kinase 2 (JAK2) by chromosomal translocations or point mutations is a frequent event in haematological malignancies. JAK2 is a non-receptor tyrosine kinase that regulates several cellular processes by inducing cytoplasmic signalling cascades. Here we show that human JAK2 is present in the nucleus of haematopoietic cells and directly phosphorylates Tyr 41 (Y41) on histone H3. Heterochromatin protein 1alpha (HP1alpha), but not HP1beta, specifically binds to this region of H3 through its chromo-shadow domain. Phosphorylation of H3Y41 by JAK2 prevents this binding. Inhibition of JAK2 activity in human leukaemic cells decreases both the expression of the haematopoietic oncogene lmo2 and the phosphorylation of H3Y41 at its promoter, while simultaneously increasing the binding of HP1alpha at the same site. Tauhese results identify a previously unrecognized nuclear role for JAK2 in the phosphorylation of H3Y41 and reveal a direct mechanistic link between two genes, jak2 and lmo2, involved in normal haematopoiesis and leukaemia.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3785147/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3785147/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dawson, Mark A -- Bannister, Andrew J -- Gottgens, Berthold -- Foster, Samuel D -- Bartke, Till -- Green, Anthony R -- Kouzarides, Tony -- 089957/Wellcome Trust/United Kingdom -- 12765/Cancer Research UK/United Kingdom -- G0800784/Medical Research Council/United Kingdom -- MC_UP_1102/2/Medical Research Council/United Kingdom -- Cancer Research UK/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2009 Oct 8;461(7265):819-22. doi: 10.1038/nature08448. Epub 2009 Sep 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cambridge Institute for Medical Research and Department of Haematology, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19783980" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing ; Animals ; Binding Sites ; Cell Line ; Cell Nucleus/enzymology ; Chromatin/chemistry/*metabolism ; Chromosomal Proteins, Non-Histone/*metabolism ; DNA-Binding Proteins/genetics ; Gene Expression Regulation, Neoplastic ; Hematopoiesis/genetics ; Hematopoietic Stem Cells/cytology/enzymology ; Histones/chemistry/genetics/*metabolism ; Humans ; Janus Kinase 2/antagonists & inhibitors/*metabolism ; LIM Domain Proteins ; Leukemia/enzymology/genetics/metabolism/pathology ; Metalloproteins/genetics ; Mice ; Oncogenes/genetics ; Phosphorylation ; Promoter Regions, Genetic/genetics ; Protein Binding ; Proto-Oncogene Proteins ; Signal Transduction ; Tyrosine/metabolism
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  • 13
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    Crystal structure of an avian influenza polymerase PA(N) reveals an endonuclease active site (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-02-06
    Description: The heterotrimeric influenza virus polymerase, containing the PA, PB1 and PB2 proteins, catalyses viral RNA replication and transcription in the nucleus of infected cells. PB1 holds the polymerase active site and reportedly harbours endonuclease activity, whereas PB2 is responsible for cap binding. The PA amino terminus is understood to be the major functional part of the PA protein and has been implicated in several roles, including endonuclease and protease activities as well as viral RNA/complementary RNA promoter binding. Here we report the 2.2 angstrom (A) crystal structure of the N-terminal 197 residues of PA, termed PA(N), from an avian influenza H5N1 virus. The PA(N) structure has an alpha/beta architecture and reveals a bound magnesium ion coordinated by a motif similar to the (P)DX(N)(D/E)XK motif characteristic of many endonucleases. Structural comparisons and mutagenesis analysis of the motif identified in PA(N) provide further evidence that PA(N) holds an endonuclease active site. Furthermore, functional analysis with in vivo ribonucleoprotein reconstitution and direct in vitro endonuclease assays strongly suggest that PA(N) holds the endonuclease active site and has critical roles in endonuclease activity of the influenza virus polymerase, rather than PB1. The high conservation of this endonuclease active site among influenza strains indicates that PA(N) is an important target for the design of new anti-influenza therapeutics.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yuan, Puwei -- Bartlam, Mark -- Lou, Zhiyong -- Chen, Shoudeng -- Zhou, Jie -- He, Xiaojing -- Lv, Zongyang -- Ge, Ruowen -- Li, Xuemei -- Deng, Tao -- Fodor, Ervin -- Rao, Zihe -- Liu, Yingfang -- G0700848/Medical Research Council/United Kingdom -- England -- Nature. 2009 Apr 16;458(7240):909-13. doi: 10.1038/nature07720. Epub 2009 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19194458" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Birds/virology ; Catalytic Domain ; Crystallography, X-Ray ; Endonucleases/*chemistry/genetics/*metabolism ; Influenza A Virus, H5N1 Subtype/*enzymology ; Influenza in Birds/*virology ; Models, Molecular ; Protein Subunits/chemistry/genetics/metabolism ; RNA Replicase/*chemistry/genetics/*metabolism ; Viral Proteins/*chemistry/genetics/*metabolism
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  • 14
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    Design of protein-interaction specificity gives selective bZIP-binding peptides (2009)
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    Publication Date: 2009-04-17
    Description: Interaction specificity is a required feature of biological networks and a necessary characteristic of protein or small-molecule reagents and therapeutics. The ability to alter or inhibit protein interactions selectively would advance basic and applied molecular science. Assessing or modelling interaction specificity requires treating multiple competing complexes, which presents computational and experimental challenges. Here we present a computational framework for designing protein-interaction specificity and use it to identify specific peptide partners for human basic-region leucine zipper (bZIP) transcription factors. Protein microarrays were used to characterize designed, synthetic ligands for all but one of 20 bZIP families. The bZIP proteins share strong sequence and structural similarities and thus are challenging targets to bind specifically. Nevertheless, many of the designs, including examples that bind the oncoproteins c-Jun, c-Fos and c-Maf (also called JUN, FOS and MAF, respectively), were selective for their targets over all 19 other families. Collectively, the designs exhibit a wide range of interaction profiles and demonstrate that human bZIPs have only sparsely sampled the possible interaction space accessible to them. Our computational method provides a way to systematically analyse trade-offs between stability and specificity and is suitable for use with many types of structure-scoring functions; thus, it may prove broadly useful as a tool for protein design.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748673/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748673/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grigoryan, Gevorg -- Reinke, Aaron W -- Keating, Amy E -- GM67681/GM/NIGMS NIH HHS/ -- R01 GM067681/GM/NIGMS NIH HHS/ -- R01 GM067681-04/GM/NIGMS NIH HHS/ -- R01 GM067681-05/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Apr 16;458(7240):859-64. doi: 10.1038/nature07885.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MIT Department of Biology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19370028" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Basic-Leucine Zipper Transcription Factors/*chemistry/classification/*metabolism ; Computational Biology/*methods ; Drug Design ; Humans ; Leucine Zippers ; Protein Array Analysis ; Protein Binding ; Protein Engineering/*methods ; Reproducibility of Results ; Substrate Specificity
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    Chaperone-mediated pathway of proteasome regulatory particle assembly (2009)
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    Publication Date: 2009-05-05
    Description: The proteasome is a protease that controls diverse processes in eukaryotic cells. Its regulatory particle (RP) initiates the degradation of ubiquitin-protein conjugates by unfolding the substrate and translocating it into the proteasome core particle (CP) to be degraded. The RP has 19 subunits, and their pathway of assembly is not understood. Here we show that in the yeast Saccharomyces cerevisiae three proteins are found associated with RP but not with the RP-CP holoenzyme: Nas6, Rpn14 and Hsm3. Mutations in the corresponding genes confer proteasome loss-of-function phenotypes, despite their virtual absence from the holoenzyme. These effects result from deficient RP assembly. Thus, Nas6, Rpn14 and Hsm3 are RP chaperones. The RP contains six ATPases-the Rpt proteins-and each RP chaperone binds to the carboxy-terminal domain of a specific Rpt. We show in an accompanying study that RP assembly is templated through the Rpt C termini, apparently by their insertion into binding pockets in the CP. Thus, RP chaperones may regulate proteasome assembly by directly restricting the accessibility of Rpt C termini to the CP. In addition, competition between the RP chaperones and the CP for Rpt engagement may explain the release of RP chaperones as proteasomes mature.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727592/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727592/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Roelofs, Jeroen -- Park, Soyeon -- Haas, Wilhelm -- Tian, Geng -- McAllister, Fiona E -- Huo, Ying -- Lee, Byung-Hoon -- Zhang, Fan -- Shi, Yigong -- Gygi, Steven P -- Finley, Daniel -- 5F32GM75737-2/GM/NIGMS NIH HHS/ -- GM043601/GM/NIGMS NIH HHS/ -- GM67945/GM/NIGMS NIH HHS/ -- R37 GM043601/GM/NIGMS NIH HHS/ -- R37 GM043601-19/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Jun 11;459(7248):861-5. doi: 10.1038/nature08063.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19412159" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/chemistry/metabolism ; Carrier Proteins/genetics/metabolism ; Conserved Sequence ; Evolution, Molecular ; Holoenzymes/chemistry/metabolism ; Humans ; Models, Molecular ; Molecular Chaperones/genetics/*metabolism ; Mutation ; Phenotype ; Proteasome Endopeptidase Complex/*chemistry/genetics/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Proto-Oncogene Proteins/genetics/metabolism ; Saccharomyces cerevisiae/*enzymology/genetics ; Saccharomyces cerevisiae Proteins/genetics/metabolism
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    Bacteria hijack integrin-linked kinase to stabilize focal adhesions and block cell detachment (2009)
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    Publication Date: 2009-06-03
    Description: The rapid turnover and exfoliation of mucosal epithelial cells provides an innate defence system against bacterial infection. Nevertheless, many pathogenic bacteria, including Shigella, are able to surmount exfoliation and colonize the epithelium efficiently. Here we show that the Shigella flexneri effector OspE (consisting of OspE1 and OspE2 proteins), which is highly conserved among enteropathogenic Escherichia coli, enterohaemorrhagic E. coli, Citrobacter rodentium and Salmonella strains, reinforces host cell adherence to the basement membrane by interacting with integrin-linked kinase (ILK). The number of focal adhesions was augmented along with membrane fraction ILK by ILK-OspE binding. The interaction between ILK and OspE increased cell surface levels of 1 integrin and suppressed phosphorylation of focal adhesion kinase and paxillin, which are required for rapid turnover of focal adhesion in cell motility. Nocodazole-washout-induced focal adhesion disassembly was blocked by expression of OspE. Polarized epithelial cells infected with a Shigella mutant lacking the ospE gene underwent more rapid cell detachment than cells infected with wild-type Shigella. Infection of guinea pig colons with Shigella corroborated the pivotal role of the OspE-ILK interaction in suppressing epithelial detachment, increasing bacterial cell-to-cell spreading, and promoting bacterial colonization. These results indicate that Shigella sustain their infectious foothold by using special tactics to prevent detachment of infected cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Minsoo -- Ogawa, Michinaga -- Fujita, Yukihiro -- Yoshikawa, Yuko -- Nagai, Takeshi -- Koyama, Tomohiro -- Nagai, Shinya -- Lange, Anika -- Fassler, Reinhard -- Sasakawa, Chihiro -- England -- Nature. 2009 May 28;459(7246):578-82. doi: 10.1038/nature07952.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Infectious Disease Control, International Research Center for Infectious Diseases, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19489119" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD29/metabolism ; Bacterial Outer Membrane Proteins/genetics/metabolism ; Cell Adhesion/drug effects/*physiology ; Cell Polarity ; Colon/microbiology ; Epithelial Cells/cytology/microbiology ; Focal Adhesions/drug effects/*physiology ; Guinea Pigs ; HeLa Cells ; Humans ; Mice ; Nocodazole/pharmacology ; Phosphorylation ; Protein Binding ; Protein-Serine-Threonine Kinases/*metabolism ; Shigella flexneri/pathogenicity/*physiology ; Virulence Factors/deficiency/genetics/metabolism
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    A newly discovered protein export machine in malaria parasites (2009)
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    Publication Date: 2009-06-19
    Description: Several hundred malaria parasite proteins are exported beyond an encasing vacuole and into the cytosol of the host erythrocyte, a process that is central to the virulence and viability of the causative Plasmodium species. The trafficking machinery responsible for this export is unknown. Here we identify in Plasmodium falciparum a translocon of exported proteins (PTEX), which is located in the vacuole membrane. The PTEX complex is ATP-powered, and comprises heat shock protein 101 (HSP101; a ClpA/B-like ATPase from the AAA+ superfamily, of a type commonly associated with protein translocons), a novel protein termed PTEX150 and a known parasite protein, exported protein 2 (EXP2). EXP2 is the potential channel, as it is the membrane-associated component of the core PTEX complex. Two other proteins, a new protein PTEX88 and thioredoxin 2 (TRX2), were also identified as PTEX components. As a common portal for numerous crucial processes, this translocon offers a new avenue for therapeutic intervention.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2725363/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2725363/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉de Koning-Ward, Tania F -- Gilson, Paul R -- Boddey, Justin A -- Rug, Melanie -- Smith, Brian J -- Papenfuss, Anthony T -- Sanders, Paul R -- Lundie, Rachel J -- Maier, Alexander G -- Cowman, Alan F -- Crabb, Brendan S -- R01 AI044008-11/AI/NIAID NIH HHS/ -- R01 AI44008/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Jun 18;459(7249):945-9. doi: 10.1038/nature08104.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Walter & Eliza Hall Institute of Medical Research, Melbourne 3052, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19536257" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Genetically Modified ; Malaria, Falciparum/*parasitology ; Models, Biological ; Multiprotein Complexes/*chemistry/*metabolism ; Plasmodium falciparum/*metabolism ; Protein Binding ; Protein Transport ; Protozoan Proteins/*metabolism
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    The role of DNA shape in protein-DNA recognition (2009)
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    Publication Date: 2009-10-30
    Description: The recognition of specific DNA sequences by proteins is thought to depend on two types of mechanism: one that involves the formation of hydrogen bonds with specific bases, primarily in the major groove, and one involving sequence-dependent deformations of the DNA helix. By comprehensively analysing the three-dimensional structures of protein-DNA complexes, here we show that the binding of arginine residues to narrow minor grooves is a widely used mode for protein-DNA recognition. This readout mechanism exploits the phenomenon that narrow minor grooves strongly enhance the negative electrostatic potential of the DNA. The nucleosome core particle offers a prominent example of this effect. Minor-groove narrowing is often associated with the presence of A-tracts, AT-rich sequences that exclude the flexible TpA step. These findings indicate that the ability to detect local variations in DNA shape and electrostatic potential is a general mechanism that enables proteins to use information in the minor groove, which otherwise offers few opportunities for the formation of base-specific hydrogen bonds, to achieve DNA-binding specificity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2793086/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2793086/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rohs, Remo -- West, Sean M -- Sosinsky, Alona -- Liu, Peng -- Mann, Richard S -- Honig, Barry -- GM54510/GM/NIGMS NIH HHS/ -- R01 GM030518/GM/NIGMS NIH HHS/ -- U54 CA121852/CA/NCI NIH HHS/ -- U54 CA121852-05/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Oct 29;461(7268):1248-53. doi: 10.1038/nature08473.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Center for Computational Biology and Bioinformatics, Department of Biochemistry and Molecular Biophysics, Columbia University, 1130 Saint Nicholas Avenue, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19865164" target="_blank"〉PubMed〈/a〉
    Keywords: AT Rich Sequence/genetics ; Animals ; Arginine/metabolism ; Base Sequence ; DNA/*chemistry/genetics/*metabolism ; DNA-Binding Proteins/chemistry/*metabolism ; Databases, Factual ; Hydrogen Bonding ; Lysine ; *Nucleic Acid Conformation ; Nucleosomes/chemistry/metabolism ; Protein Binding ; Saccharomyces cerevisiae ; Static Electricity
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    Structural biology: Inside the living cell (2009)
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    Publication Date: 2009-03-06
    Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4440453/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4440453/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Burz, David S -- Shekhtman, Alexander -- R01 GM085006/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Mar 5;458(7234):37-8. doi: 10.1038/458037a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19262658" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bacterial Proteins/chemistry/genetics ; Drug Evaluation, Preclinical/methods ; Escherichia coli/*cytology/genetics/*metabolism ; Humans ; Intracellular Space/*metabolism ; Nuclear Magnetic Resonance, Biomolecular/*methods ; Oocytes/metabolism ; Protein Binding ; Thermus thermophilus/genetics ; Xenopus laevis
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    Structural basis of abscisic acid signalling (2009)
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    Publication Date: 2009-10-27
    Description: The phytohormone abscisic acid (ABA) mediates the adaptation of plants to environmental stresses such as drought and regulates developmental signals such as seed maturation. Within plants, the PYR/PYL/RCAR family of START proteins receives ABA to inhibit the phosphatase activity of the group-A protein phosphatases 2C (PP2Cs), which are major negative regulators in ABA signalling. Here we present the crystal structures of the ABA receptor PYL1 bound with (+)-ABA, and the complex formed by the further binding of (+)-ABA-bound PYL1 with the PP2C protein ABI1. PYL1 binds (+)-ABA using the START-protein-specific ligand-binding site, thereby forming a hydrophobic pocket on the surface of the closed lid. (+)-ABA-bound PYL1 tightly interacts with a PP2C domain of ABI1 by using the hydrophobic pocket to cover the active site of ABI1 like a plug. Our results reveal the structural basis of the mechanism of (+)-ABA-dependent inhibition of ABI1 by PYL1 in ABA signalling.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miyazono, Ken-Ichi -- Miyakawa, Takuya -- Sawano, Yoriko -- Kubota, Keiko -- Kang, Hee-Jin -- Asano, Atsuko -- Miyauchi, Yumiko -- Takahashi, Mihoko -- Zhi, Yuehua -- Fujita, Yasunari -- Yoshida, Takuya -- Kodaira, Ken-Suke -- Yamaguchi-Shinozaki, Kazuko -- Tanokura, Masaru -- England -- Nature. 2009 Dec 3;462(7273):609-14. doi: 10.1038/nature08583.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19855379" target="_blank"〉PubMed〈/a〉
    Keywords: Abscisic Acid/*physiology ; Arabidopsis/*physiology ; Arabidopsis Proteins/*chemistry/*metabolism ; Binding Sites ; *Models, Molecular ; Protein Binding ; Protein Structure, Tertiary ; Recombinant Proteins/chemistry/metabolism ; *Signal Transduction
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    Structural biology: Molecular coin slots for urea (2009)
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    Publication Date: 2009-12-17
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Knepper, Mark A -- Mindell, Joseph A -- England -- Nature. 2009 Dec 10;462(7274):733-4. doi: 10.1038/462733a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20010678" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Desulfovibrio vulgaris/*chemistry ; Humans ; Kidney/metabolism ; Membrane Transport Proteins/*chemistry/*metabolism ; Protein Structure, Quaternary ; Structure-Activity Relationship ; Urea/chemistry/*metabolism
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    Exploitation of binding energy for catalysis and design (2009)
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    Publication Date: 2009-10-30
    Description: Enzymes use substrate-binding energy both to promote ground-state association and to stabilize the reaction transition state selectively. The monomeric homing endonuclease I-AniI cleaves with high sequence specificity in the centre of a 20-base-pair (bp) DNA target site, with the amino (N)-terminal domain of the enzyme making extensive binding interactions with the left (-) side of the target site and the similarly structured carboxy (C)-terminal domain interacting with the right (+) side. Here we show that, despite the approximate twofold symmetry of the enzyme-DNA complex, there is almost complete segregation of interactions responsible for substrate binding to the (-) side of the interface and interactions responsible for transition-state stabilization to the (+) side. Although single base-pair substitutions throughout the entire DNA target site reduce catalytic efficiency, mutations in the (-) DNA half-site almost exclusively increase the dissociation constant (K(D)) and the Michaelis constant under single-turnover conditions (K(M)*), and those in the (+) half-site primarily decrease the turnover number (k(cat)*). The reduction of activity produced by mutations on the (-) side, but not mutations on the (+) side, can be suppressed by tethering the substrate to the endonuclease displayed on the surface of yeast. This dramatic asymmetry in the use of enzyme-substrate binding energy for catalysis has direct relevance to the redesign of endonucleases to cleave genomic target sites for gene therapy and other applications. Computationally redesigned enzymes that achieve new specificities on the (-) side do so by modulating K(M)*, whereas redesigns with altered specificities on the (+) side modulate k(cat)*. Our results illustrate how classical enzymology and modern protein design can each inform the other.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2771326/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2771326/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Thyme, Summer B -- Jarjour, Jordan -- Takeuchi, Ryo -- Havranek, James J -- Ashworth, Justin -- Scharenberg, Andrew M -- Stoddard, Barry L -- Baker, David -- GM084433/GM/NIGMS NIH HHS/ -- R00 RR024107/RR/NCRR NIH HHS/ -- R00 RR024107-03/RR/NCRR NIH HHS/ -- R00 RR024107-04/RR/NCRR NIH HHS/ -- RL1 GM084433/GM/NIGMS NIH HHS/ -- RL1 GM084433-03/GM/NIGMS NIH HHS/ -- RL1CA133832/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Oct 29;461(7268):1300-4. doi: 10.1038/nature08508.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA. sthyme@u.washington.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19865174" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; *Biocatalysis ; Computational Biology ; *Computer Simulation ; DNA/chemistry/metabolism ; Endonucleases/chemistry/*metabolism ; Kinetics ; Models, Molecular ; Protein Binding ; Protein Conformation ; RNA-Directed DNA Polymerase/chemistry/*metabolism ; Saccharomyces cerevisiae/metabolism ; Substrate Specificity ; *Thermodynamics
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    From molecular to macroscopic via the rational design of a self-assembled 3D DNA crystal (2009)
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    Publication Date: 2009-09-04
    Description: We live in a macroscopic three-dimensional (3D) world, but our best description of the structure of matter is at the atomic and molecular scale. Understanding the relationship between the two scales requires a bridge from the molecular world to the macroscopic world. Connecting these two domains with atomic precision is a central goal of the natural sciences, but it requires high spatial control of the 3D structure of matter. The simplest practical route to producing precisely designed 3D macroscopic objects is to form a crystalline arrangement by self-assembly, because such a periodic array has only conceptually simple requirements: a motif that has a robust 3D structure, dominant affinity interactions between parts of the motif when it self-associates, and predictable structures for these affinity interactions. Fulfilling these three criteria to produce a 3D periodic system is not easy, but should readily be achieved with well-structured branched DNA motifs tailed by sticky ends. Complementary sticky ends associate with each other preferentially and assume the well-known B-DNA structure when they do so; the helically repeating nature of DNA facilitates the construction of a periodic array. It is essential that the directions of propagation associated with the sticky ends do not share the same plane, but extend to form a 3D arrangement of matter. Here we report the crystal structure at 4 A resolution of a designed, self-assembled, 3D crystal based on the DNA tensegrity triangle. The data demonstrate clearly that it is possible to design and self-assemble a well-ordered macromolecular 3D crystalline lattice with precise control.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2764300/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2764300/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zheng, Jianping -- Birktoft, Jens J -- Chen, Yi -- Wang, Tong -- Sha, Ruojie -- Constantinou, Pamela E -- Ginell, Stephan L -- Mao, Chengde -- Seeman, Nadrian C -- 1R21EB007472/EB/NIBIB NIH HHS/ -- R21 EB007472/EB/NIBIB NIH HHS/ -- R21 EB007472-03/EB/NIBIB NIH HHS/ -- England -- Nature. 2009 Sep 3;461(7260):74-7. doi: 10.1038/nature08274.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, New York University, New York 10003, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19727196" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Crystallization ; Crystallography, X-Ray ; DNA/*chemistry/genetics ; *Drug Design ; Molecular Sequence Data ; *Nucleic Acid Conformation
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    An unusual mechanism of thymidylate biosynthesis in organisms containing the thyX gene (2009)
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    Publication Date: 2009-04-17
    Description: Biosynthesis of the DNA base thymine depends on activity of the enzyme thymidylate synthase to catalyse the methylation of the uracil moiety of 2'-deoxyuridine-5'-monophosphate. All known thymidylate synthases rely on an active site residue of the enzyme to activate 2'-deoxyuridine-5'-monophosphate. This functionality has been demonstrated for classical thymidylate synthases, including human thymidylate synthase, and is instrumental in mechanism-based inhibition of these enzymes. Here we report an example of thymidylate biosynthesis that occurs without an enzymatic nucleophile. This unusual biosynthetic pathway occurs in organisms containing the thyX gene, which codes for a flavin-dependent thymidylate synthase (FDTS), and is present in several human pathogens. Our findings indicate that the putative active site nucleophile is not required for FDTS catalysis, and no alternative nucleophilic residues capable of serving this function can be identified. Instead, our findings suggest that a hydride equivalent (that is, a proton and two electrons) is transferred from the reduced flavin cofactor directly to the uracil ring, followed by an isomerization of the intermediate to form the product, 2'-deoxythymidine-5'-monophosphate. These observations indicate a very different chemical cascade than that of classical thymidylate synthases or any other known biological methylation. The findings and chemical mechanism proposed here, together with available structural data, suggest that selective inhibition of FDTSs, with little effect on human thymine biosynthesis, should be feasible. Because several human pathogens depend on FDTS for DNA biosynthesis, its unique mechanism makes it an attractive target for antibiotic drugs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2759699/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2759699/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Koehn, Eric M -- Fleischmann, Todd -- Conrad, John A -- Palfey, Bruce A -- Lesley, Scott A -- Mathews, Irimpan I -- Kohen, Amnon -- GM08270/GM/NIGMS NIH HHS/ -- R01 GM065368/GM/NIGMS NIH HHS/ -- R01 GM065368-05/GM/NIGMS NIH HHS/ -- R01 GM61087/GM/NIGMS NIH HHS/ -- U54GM074898/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Apr 16;458(7240):919-23. doi: 10.1038/nature07973.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19370033" target="_blank"〉PubMed〈/a〉
    Keywords: Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; Deoxyuracil Nucleotides/chemistry/metabolism ; Deuterium/metabolism ; Electrons ; Flavin-Adenine Dinucleotide/chemistry/metabolism ; Flavins/chemistry/*metabolism ; Helicobacter pylori/enzymology ; Humans ; Magnetic Resonance Spectroscopy ; Methylation ; Models, Molecular ; Mycobacterium tuberculosis/enzymology ; Protons ; Thermotoga maritima/*enzymology/*metabolism ; Thymidine/analogs & derivatives/metabolism ; Thymidine Monophosphate/*biosynthesis ; Thymidylate Synthase/antagonists & inhibitors/*genetics/*metabolism ; Uracil/metabolism
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    Cooperative binding of two acetylation marks on a histone tail by a single bromodomain (2009)
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    Publication Date: 2009-10-02
    Description: A key step in many chromatin-related processes is the recognition of histone post-translational modifications by effector modules such as bromodomains and chromo-like domains of the Royal family. Whereas effector-mediated recognition of single post-translational modifications is well characterized, how the cell achieves combinatorial readout of histones bearing multiple modifications is poorly understood. One mechanism involves multivalent binding by linked effector modules. For example, the tandem bromodomains of human TATA-binding protein-associated factor-1 (TAF1) bind better to a diacetylated histone H4 tail than to monoacetylated tails, a cooperative effect attributed to each bromodomain engaging one acetyl-lysine mark. Here we report a distinct mechanism of combinatorial readout for the mouse TAF1 homologue Brdt, a testis-specific member of the BET protein family. Brdt associates with hyperacetylated histone H4 (ref. 7) and is implicated in the marked chromatin remodelling that follows histone hyperacetylation during spermiogenesis, the stage of spermatogenesis in which post-meiotic germ cells mature into fully differentiated sperm. Notably, we find that a single bromodomain (BD1) of Brdt is responsible for selectively recognizing histone H4 tails bearing two or more acetylation marks. The crystal structure of BD1 bound to a diacetylated H4 tail shows how two acetyl-lysine residues cooperate to interact with one binding pocket. Structure-based mutagenesis that reduces the selectivity of BD1 towards diacetylated tails destabilizes the association of Brdt with acetylated chromatin in vivo. Structural analysis suggests that other chromatin-associated proteins may be capable of a similar mode of ligand recognition, including yeast Bdf1, human TAF1 and human CBP/p300 (also known as CREBBP and EP300, respectively). Our findings describe a new mechanism for the combinatorial readout of histone modifications in which a single effector module engages two marks on a histone tail as a composite binding epitope.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moriniere, Jeanne -- Rousseaux, Sophie -- Steuerwald, Ulrich -- Soler-Lopez, Montserrat -- Curtet, Sandrine -- Vitte, Anne-Laure -- Govin, Jerome -- Gaucher, Jonathan -- Sadoul, Karin -- Hart, Darren J -- Krijgsveld, Jeroen -- Khochbin, Saadi -- Muller, Christoph W -- Petosa, Carlo -- England -- Nature. 2009 Oct 1;461(7264):664-8. doi: 10.1038/nature08397.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉European Molecular Biology Laboratory, Grenoble Outstation, 6 rue Jules Horowitz, BP 181, 38042 Grenoble Cedex 9, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19794495" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Allosteric Regulation ; Animals ; Binding Sites ; COS Cells ; Cercopithecus aethiops ; Chromatin/chemistry/metabolism ; Crystallography, X-Ray ; Histones/*chemistry/*metabolism ; Lysine/metabolism ; Mice ; Models, Molecular ; Nuclear Proteins/*chemistry/genetics/*metabolism ; Protein Binding ; Protein Conformation ; Protein Structure, Tertiary ; Substrate Specificity
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    Combinatorial binding predicts spatio-temporal cis-regulatory activity (2009)
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    Publication Date: 2009-11-06
    Description: Development requires the establishment of precise patterns of gene expression, which are primarily controlled by transcription factors binding to cis-regulatory modules. Although transcription factor occupancy can now be identified at genome-wide scales, decoding this regulatory landscape remains a daunting challenge. Here we used a novel approach to predict spatio-temporal cis-regulatory activity based only on in vivo transcription factor binding and enhancer activity data. We generated a high-resolution atlas of cis-regulatory modules describing their temporal and combinatorial occupancy during Drosophila mesoderm development. The binding profiles of cis-regulatory modules with characterized expression were used to train support vector machines to predict five spatio-temporal expression patterns. In vivo transgenic reporter assays demonstrate the high accuracy of these predictions and reveal an unanticipated plasticity in transcription factor binding leading to similar expression. This data-driven approach does not require previous knowledge of transcription factor sequence affinity, function or expression, making it widely applicable.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zinzen, Robert P -- Girardot, Charles -- Gagneur, Julien -- Braun, Martina -- Furlong, Eileen E M -- England -- Nature. 2009 Nov 5;462(7269):65-70. doi: 10.1038/nature08531.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉European Molecular Biology Laboratory, D-69117 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19890324" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Genetically Modified ; Artificial Intelligence ; Chromatin Immunoprecipitation ; Conserved Sequence/genetics ; Databases, Genetic ; Drosophila melanogaster/*embryology/*genetics ; Enhancer Elements, Genetic/genetics ; *Gene Expression Regulation, Developmental/genetics ; Genes, Reporter/genetics ; Mesoderm/embryology/metabolism ; *Models, Genetic ; Protein Binding ; Time Factors ; Transcription Factors/*metabolism
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    Substrate interactions and promiscuity in a viral DNA packaging motor (2009)
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    Publication Date: 2009-10-02
    Description: The ASCE (additional strand, conserved E) superfamily of proteins consists of structurally similar ATPases associated with diverse cellular activities involving metabolism and transport of proteins and nucleic acids in all forms of life. A subset of these enzymes consists of multimeric ringed pumps responsible for DNA transport in processes including genome packaging in adenoviruses, herpesviruses, poxviruses and tailed bacteriophages. Although their mechanism of mechanochemical conversion is beginning to be understood, little is known about how these motors engage their nucleic acid substrates. Questions remain as to whether the motors contact a single DNA element, such as a phosphate or a base, or whether contacts are distributed over several parts of the DNA. Furthermore, the role of these contacts in the mechanochemical cycle is unknown. Here we use the genome packaging motor of the Bacillus subtilis bacteriophage varphi29 (ref. 4) to address these questions. The full mechanochemical cycle of the motor, in which the ATPase is a pentameric-ring of gene product 16 (gp16), involves two phases-an ATP-loading dwell followed by a translocation burst of four 2.5-base-pair (bp) steps triggered by hydrolysis product release. By challenging the motor with a variety of modified DNA substrates, we show that during the dwell phase important contacts are made with adjacent phosphates every 10-bp on the 5'-3' strand in the direction of packaging. As well as providing stable, long-lived contacts, these phosphate interactions also regulate the chemical cycle. In contrast, during the burst phase, we find that DNA translocation is driven against large forces by extensive contacts, some of which are not specific to the chemical moieties of DNA. Such promiscuous, nonspecific contacts may reflect common translocase-substrate interactions for both the nucleic acid and protein translocases of the ASCE superfamily.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769991/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769991/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Aathavan, K -- Politzer, Adam T -- Kaplan, Ariel -- Moffitt, Jeffrey R -- Chemla, Yann R -- Grimes, Shelley -- Jardine, Paul J -- Anderson, Dwight L -- Bustamante, Carlos -- DE-003606/DE/NIDCR NIH HHS/ -- GM-059604/GM/NIGMS NIH HHS/ -- GM-071552/GM/NIGMS NIH HHS/ -- R01 GM059604/GM/NIGMS NIH HHS/ -- R01 GM059604-09A1/GM/NIGMS NIH HHS/ -- R01 GM071552/GM/NIGMS NIH HHS/ -- R01 GM071552-04/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Oct 1;461(7264):669-73. doi: 10.1038/nature08443.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Biophysics Graduate Group, University of California, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19794496" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/chemistry/*metabolism ; Adenosine Triphosphate/metabolism ; Bacillus Phages/enzymology/genetics/*metabolism ; Bacillus subtilis/*virology ; Biological Transport ; DNA, Viral/chemistry/*metabolism ; DNA-Binding Proteins/chemistry/metabolism ; Genome, Viral ; Hydrolysis ; Molecular Motor Proteins/chemistry/*metabolism ; Phosphates/metabolism ; Protein Binding ; Substrate Specificity ; Viral Proteins/chemistry/*metabolism ; Virus Assembly/*physiology
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    The structure of a cytolytic alpha-helical toxin pore reveals its assembly mechanism (2009)
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    Publication Date: 2009-05-08
    Description: Pore-forming toxins (PFTs) are a class of potent virulence factors that convert from a soluble form to a membrane-integrated pore. They exhibit their toxic effect either by destruction of the membrane permeability barrier or by delivery of toxic components through the pores. Among the group of bacterial PFTs are some of the most dangerous toxins, such as diphtheria and anthrax toxin. Examples of eukaryotic PFTs are perforin and the membrane-attack complex, proteins of the immune system. PFTs can be subdivided into two classes, alpha-PFTs and beta-PFTs, depending on the suspected mode of membrane integration, either by alpha-helical or beta-sheet elements. The only high-resolution structure of a transmembrane PFT pore is available for a beta-PFT--alpha-haemolysin from Staphylococcus aureus. Cytolysin A (ClyA, also known as HlyE), an alpha-PFT, is a cytolytic -helical toxin responsible for the haemolytic phenotype of several Escherichia coli and Salmonella enterica strains. ClyA is cytotoxic towards cultured mammalian cells, induces apoptosis of macrophages and promotes tissue pervasion. Electron microscopic reconstructions demonstrated that the soluble monomer of ClyA must undergo large conformational changes to form the transmembrane pore. Here we report the 3.3 A crystal structure of the 400 kDa dodecameric transmembrane pore formed by ClyA. The tertiary structure of ClyA protomers in the pore is substantially different from that in the soluble monomer. The conversion involves more than half of all residues. It results in large rearrangements, up to 140 A, of parts of the monomer, reorganization of the hydrophobic core, and transitions of -sheets and loop regions to -helices. The large extent of interdependent conformational changes indicates a sequential mechanism for membrane insertion and pore formation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mueller, Marcus -- Grauschopf, Ulla -- Maier, Timm -- Glockshuber, Rudi -- Ban, Nenad -- England -- Nature. 2009 Jun 4;459(7247):726-30. doi: 10.1038/nature08026.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19421192" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Membrane/chemistry ; Crystallography, X-Ray ; Escherichia coli K12/*chemistry ; Escherichia coli Proteins/*chemistry ; Hemolysin Proteins/*chemistry ; Membrane Proteins/*chemistry ; *Models, Molecular ; *Protein Folding ; Protein Structure, Tertiary
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    Structural basis for leucine-rich nuclear export signal recognition by CRM1 (2009)
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    Publication Date: 2009-04-03
    Description: CRM1 (also known as XPO1 and exportin 1) mediates nuclear export of hundreds of proteins through the recognition of the leucine-rich nuclear export signal (LR-NES). Here we present the 2.9 A structure of CRM1 bound to snurportin 1 (SNUPN). Snurportin 1 binds CRM1 in a bipartite manner by means of an amino-terminal LR-NES and its nucleotide-binding domain. The LR-NES is a combined alpha-helical-extended structure that occupies a hydrophobic groove between two CRM1 outer helices. The LR-NES interface explains the consensus hydrophobic pattern, preference for intervening electronegative residues and inhibition by leptomycin B. The second nuclear export signal epitope is a basic surface on the snurportin 1 nucleotide-binding domain, which binds an acidic patch on CRM1 adjacent to the LR-NES site. Multipartite recognition of individually weak nuclear export signal epitopes may be common to CRM1 substrates, enhancing CRM1 binding beyond the generally low affinity LR-NES. Similar energetic construction is also used in multipartite nuclear localization signals to provide broad substrate specificity and rapid evolution in nuclear transport.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3437623/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3437623/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dong, Xiuhua -- Biswas, Anindita -- Suel, Katherine E -- Jackson, Laurie K -- Martinez, Rita -- Gu, Hongmei -- Chook, Yuh Min -- 5-T32-GM008297/GM/NIGMS NIH HHS/ -- R01 GM069909/GM/NIGMS NIH HHS/ -- R01GM069909/GM/NIGMS NIH HHS/ -- R01GM069909-03S1/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Apr 30;458(7242):1136-41. doi: 10.1038/nature07975. Epub 2009 Apr 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park, Dallas, Texas 75390-9041, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19339969" target="_blank"〉PubMed〈/a〉
    Keywords: Active Transport, Cell Nucleus ; Crystallography, X-Ray ; Epitopes ; Fatty Acids, Unsaturated/pharmacology ; Humans ; Hydrophobic and Hydrophilic Interactions ; Karyopherins/*chemistry/*metabolism ; Leucine/*metabolism ; Models, Molecular ; Nuclear Export Signals/*physiology ; Protein Binding/drug effects ; Protein Conformation ; Receptors, Cytoplasmic and Nuclear/*chemistry/*metabolism ; Structure-Activity Relationship ; Substrate Specificity ; snRNP Core Proteins/chemistry/metabolism
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    The pluripotency factor Oct4 interacts with Ctcf and also controls X-chromosome pairing and counting (2009)
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    Publication Date: 2009-06-19
    Description: Pluripotency of embryonic stem (ES) cells is controlled by defined transcription factors. During differentiation, mouse ES cells undergo global epigenetic reprogramming, as exemplified by X-chromosome inactivation (XCI) in which one female X chromosome is silenced to achieve gene dosage parity between the sexes. Somatic XCI is regulated by homologous X-chromosome pairing and counting, and by the random choice of future active and inactive X chromosomes. XCI and cell differentiation are tightly coupled, as blocking one process compromises the other and dedifferentiation of somatic cells to induced pluripotent stem cells is accompanied by X chromosome reactivation. Recent evidence suggests coupling of Xist expression to pluripotency factors occurs, but how the two are interconnected remains unknown. Here we show that Oct4 (also known as Pou5f1) lies at the top of the XCI hierarchy, and regulates XCI by triggering X-chromosome pairing and counting. Oct4 directly binds Tsix and Xite, two regulatory noncoding RNA genes of the X-inactivation centre, and also complexes with XCI trans-factors, Ctcf and Yy1 (ref. 17), through protein-protein interactions. Depletion of Oct4 blocks homologous X-chromosome pairing and results in the inactivation of both X chromosomes in female cells. Thus, we have identified the first trans-factor that regulates counting, and ascribed new functions to Oct4 during X-chromosome reprogramming.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057664/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057664/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Donohoe, Mary E -- Silva, Susana S -- Pinter, Stefan F -- Xu, Na -- Lee, Jeannie T -- GM58839/GM/NIGMS NIH HHS/ -- R01 GM058839/GM/NIGMS NIH HHS/ -- R01 GM058839-10/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Jul 2;460(7251):128-32. doi: 10.1038/nature08098. Epub 2009 Jun 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19536159" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; *Chromosome Pairing ; Female ; Humans ; Male ; Mice ; Octamer Transcription Factor-3/deficiency/genetics/*metabolism ; Protein Binding ; RNA, Long Noncoding ; RNA, Untranslated/genetics ; Repressor Proteins/*metabolism ; SOXB1 Transcription Factors ; Transcriptional Activation ; X Chromosome/*genetics/*metabolism ; X Chromosome Inactivation/*genetics ; YY1 Transcription Factor/metabolism
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    NAADP mobilizes calcium from acidic organelles through two-pore channels (2009)
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    Publication Date: 2009-04-24
    Description: Ca(2+) mobilization from intracellular stores represents an important cell signalling process that is regulated, in mammalian cells, by inositol-1,4,5-trisphosphate (InsP(3)), cyclic ADP ribose and nicotinic acid adenine dinucleotide phosphate (NAADP). InsP(3) and cyclic ADP ribose cause the release of Ca(2+) from sarcoplasmic/endoplasmic reticulum stores by the activation of InsP(3) and ryanodine receptors (InsP(3)Rs and RyRs). In contrast, the nature of the intracellular stores targeted by NAADP and the molecular identity of the NAADP receptors remain controversial, although evidence indicates that NAADP mobilizes Ca(2+) from lysosome-related acidic compartments. Here we show that two-pore channels (TPCs) comprise a family of NAADP receptors, with human TPC1 (also known as TPCN1) and chicken TPC3 (TPCN3) being expressed on endosomal membranes, and human TPC2 (TPCN2) on lysosomal membranes when expressed in HEK293 cells. Membranes enriched with TPC2 show high affinity NAADP binding, and TPC2 underpins NAADP-induced Ca(2+) release from lysosome-related stores that is subsequently amplified by Ca(2+)-induced Ca(2+) release by InsP(3)Rs. Responses to NAADP were abolished by disrupting the lysosomal proton gradient and by ablating TPC2 expression, but were only attenuated by depleting endoplasmic reticulum Ca(2+) stores or by blocking InsP(3)Rs. Thus, TPCs form NAADP receptors that release Ca(2+) from acidic organelles, which can trigger further Ca(2+) signals via sarcoplasmic/endoplasmic reticulum. TPCs therefore provide new insights into the regulation and organization of Ca(2+) signals in animal cells, and will advance our understanding of the physiological role of NAADP.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2761823/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2761823/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Calcraft, Peter J -- Ruas, Margarida -- Pan, Zui -- Cheng, Xiaotong -- Arredouani, Abdelilah -- Hao, Xuemei -- Tang, Jisen -- Rietdorf, Katja -- Teboul, Lydia -- Chuang, Kai-Ting -- Lin, Peihui -- Xiao, Rui -- Wang, Chunbo -- Zhu, Yingmin -- Lin, Yakang -- Wyatt, Christopher N -- Parrington, John -- Ma, Jianjie -- Evans, A Mark -- Galione, Antony -- Zhu, Michael X -- 070772/Wellcome Trust/United Kingdom -- FS/05/050/British Heart Foundation/United Kingdom -- P30 NS045758/NS/NINDS NIH HHS/ -- P30 NS045758-05/NS/NINDS NIH HHS/ -- P30 NS045758-059003/NS/NINDS NIH HHS/ -- P30-NS045758/NS/NINDS NIH HHS/ -- R01 DK081654/DK/NIDDK NIH HHS/ -- R01 DK081654-01A1/DK/NIDDK NIH HHS/ -- R01 NS042183/NS/NINDS NIH HHS/ -- R01 NS042183-04/NS/NINDS NIH HHS/ -- R21 NS056942/NS/NINDS NIH HHS/ -- R21 NS056942-01/NS/NINDS NIH HHS/ -- England -- Nature. 2009 May 28;459(7246):596-600. doi: 10.1038/nature08030. Epub 2009 Apr 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Integrative Physiology, College of Medicine and Veterinary Medicine, University of Edinburgh, Hugh Robson Building, Edinburgh EH8 9XD, Scotland, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19387438" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcium/*metabolism ; Calcium Channels/genetics/*metabolism ; *Calcium Signaling/drug effects ; Cell Line ; Chickens ; Humans ; Hydrogen-Ion Concentration ; Insulin-Secreting Cells/drug effects/metabolism ; Mice ; Mice, Knockout ; Molecular Sequence Data ; NADP/*analogs & derivatives/metabolism/pharmacology ; Organelles/drug effects/*metabolism ; Protein Binding
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    Structural basis for translational fidelity ensured by transfer RNA lysidine synthetase (2009)
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    Publication Date: 2009-10-23
    Description: Maturation of precursor transfer RNA (pre-tRNA) includes excision of the 5' leader and 3' trailer sequences, removal of introns and addition of the CCA terminus. Nucleotide modifications are incorporated at different stages of tRNA processing, after the RNA molecule adopts the proper conformation. In bacteria, tRNA(Ile2) lysidine synthetase (TilS) modifies cytidine into lysidine (L; 2-lysyl-cytidine) at the first anticodon of tRNA(Ile2) (refs 4-9). This modification switches tRNA(Ile2) from a methionine-specific to an isoleucine-specific tRNA. However, the aminoacylation of tRNA(Ile2) by methionyl-tRNA synthetase (MetRS), before the modification by TilS, might lead to the misincorporation of methionine in response to isoleucine codons. The mechanism used by bacteria to avoid this pitfall is unknown. Here we show that the TilS enzyme specifically recognizes and modifies tRNA(Ile2) in its precursor form, thereby avoiding translation errors. We identified the lysidine modification in pre-tRNA(Ile2) isolated from RNase-E-deficient Escherichia coli and did not detect mature tRNA(Ile2) lacking this modification. Our kinetic analyses revealed that TilS can modify both types of RNA molecule with comparable efficiencies. X-ray crystallography and mutational analyses revealed that TilS specifically recognizes the entire L-shape structure in pre-tRNA(Ile2) through extensive interactions coupled with sequential domain movements. Our results demonstrate how TilS prevents the recognition of tRNA(Ile2) by MetRS and achieves high specificity for its substrate. These two key points form the basis for maintaining the fidelity of isoleucine codon translation in bacteria. Our findings also provide a rationale for the necessity of incorporating specific modifications at the precursor level during tRNA biogenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nakanishi, Kotaro -- Bonnefond, Luc -- Kimura, Satoshi -- Suzuki, Tsutomu -- Ishitani, Ryuichiro -- Nureki, Osamu -- England -- Nature. 2009 Oct 22;461(7267):1144-8. doi: 10.1038/nature08474.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Kanagawa 225-8501, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19847269" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acyl-tRNA Synthetases/*chemistry/genetics/*metabolism ; Apoproteins/genetics/metabolism ; Bacillus subtilis ; Bacterial Proteins/*chemistry/genetics/*metabolism ; Base Sequence ; Catalytic Domain ; Crystallography, X-Ray ; Escherichia coli ; Geobacillus ; Kinetics ; Lysine/analogs & derivatives/metabolism ; Mass Spectrometry ; Models, Molecular ; Molecular Sequence Data ; *Protein Biosynthesis ; Pyrimidine Nucleosides/metabolism ; RNA, Transfer, Ile/genetics/metabolism ; Substrate Specificity
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    The abscisic acid receptor PYR1 in complex with abscisic acid (2009)
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    Publication Date: 2009-11-10
    Description: The plant hormone abscisic acid (ABA) has a central role in coordinating the adaptive response in situations of decreased water availability as well as the regulation of plant growth and development. Recently, a 14-member family of intracellular ABA receptors, named PYR/PYL/RCAR, has been identified. These proteins inhibit in an ABA-dependent manner the activity of a family of key negative regulators of the ABA signalling pathway: the group-A protein phosphatases type 2C (PP2Cs). Here we present the crystal structure of Arabidopsis thaliana PYR1, which consists of a dimer in which one of the subunits is bound to ABA. In the ligand-bound subunit, the loops surrounding the entry to the binding cavity fold over the ABA molecule, enclosing it inside, whereas in the empty subunit they form a channel leaving an open access to the cavity, indicating that conformational changes in these loops have a critical role in the stabilization of the hormone-receptor complex. By providing structural details on the ABA-binding pocket, this work paves the way for the development of new small molecules able to activate the plant stress response.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Santiago, Julia -- Dupeux, Florine -- Round, Adam -- Antoni, Regina -- Park, Sang-Youl -- Jamin, Marc -- Cutler, Sean R -- Rodriguez, Pedro Luis -- Marquez, Jose Antonio -- England -- Nature. 2009 Dec 3;462(7273):665-8. doi: 10.1038/nature08591. Epub 2009 Nov 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Instituto de Biologia Molecular y Celular de Plantas, Consejo Superior de Investigaciones Cientificas-Universidad Politecnica de Valencia, ES-46022 Valencia, Spain.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19898494" target="_blank"〉PubMed〈/a〉
    Keywords: Abscisic Acid/*metabolism ; Arabidopsis ; Arabidopsis Proteins/*chemistry/*metabolism ; Membrane Transport Proteins/*chemistry/*metabolism ; *Models, Molecular ; Protein Binding ; Protein Structure, Tertiary
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    A conserved ubiquitination pathway determines longevity in response to diet restriction (2009)
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    Publication Date: 2009-06-26
    Description: Dietary restriction extends longevity in diverse species, suggesting that there is a conserved mechanism for nutrient regulation and prosurvival responses. Here we show a role for the HECT (homologous to E6AP carboxy terminus) E3 ubiquitin ligase WWP-1 as a positive regulator of lifespan in Caenorhabditis elegans in response to dietary restriction. We find that overexpression of wwp-1 in worms extends lifespan by up to 20% under conditions of ad libitum feeding. This extension is dependent on the FOXA transcription factor pha-4, and independent of the FOXO transcription factor daf-16. Reduction of wwp-1 completely suppresses the extended longevity of diet-restricted animals. However, the loss of wwp-1 does not affect the long lifespan of animals with compromised mitochondrial function or reduced insulin/IGF-1 signalling. Overexpression of a mutant form of WWP-1 lacking catalytic activity suppresses the increased lifespan of diet-restricted animals, indicating that WWP-1 ubiquitin ligase activity is essential for longevity. Furthermore, we find that the E2 ubiquitin conjugating enzyme, UBC-18, is essential and specific for diet-restriction-induced longevity. UBC-18 interacts with WWP-1 and is required for the ubiquitin ligase activity of WWP-1 and the extended longevity of worms overexpressing wwp-1. Taken together, our results indicate that WWP-1 and UBC-18 function to ubiquitinate substrates that regulate diet-restriction-induced longevity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746748/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746748/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Carrano, Andrea C -- Liu, Zheng -- Dillin, Andrew -- Hunter, Tony -- AG 027463/AG/NIA NIH HHS/ -- AG 032560/AG/NIA NIH HHS/ -- CA 14195/CA/NCI NIH HHS/ -- CA 54418/CA/NCI NIH HHS/ -- CA 82683/CA/NCI NIH HHS/ -- DK 070696/DK/NIDDK NIH HHS/ -- P01 CA054418/CA/NCI NIH HHS/ -- P01 CA054418-110010/CA/NCI NIH HHS/ -- P30 CA014195/CA/NCI NIH HHS/ -- P30 CA014195-35/CA/NCI NIH HHS/ -- R01 AG027463/AG/NIA NIH HHS/ -- R01 AG027463-01A2/AG/NIA NIH HHS/ -- R01 CA082683/CA/NCI NIH HHS/ -- R01 CA082683-07/CA/NCI NIH HHS/ -- R01 CA082683-08/CA/NCI NIH HHS/ -- R01 DK070696/DK/NIDDK NIH HHS/ -- R01 DK070696-04/DK/NIDDK NIH HHS/ -- R21 AG032560/AG/NIA NIH HHS/ -- R21 AG032560-01/AG/NIA NIH HHS/ -- England -- Nature. 2009 Jul 16;460(7253):396-9. doi: 10.1038/nature08130. Epub 2009 Jun 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19553937" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Genetically Modified ; Caenorhabditis elegans/genetics/*physiology ; Caenorhabditis elegans Proteins/genetics/*metabolism ; *Caloric Restriction ; DNA-Binding Proteins/metabolism ; Heat-Shock Response ; Ligases/genetics/*metabolism ; Longevity/*physiology ; Protein Binding ; Receptors, Nicotinic/genetics/metabolism ; Trans-Activators/genetics/metabolism ; Transcription Factors/metabolism ; Ubiquitin-Protein Ligases/genetics/*metabolism ; Ubiquitination/*physiology
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    Flipping of alkylated DNA damage bridges base and nucleotide excision repair (2009)
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    Publication Date: 2009-06-12
    Description: Alkyltransferase-like proteins (ATLs) share functional motifs with the cancer chemotherapy target O(6)-alkylguanine-DNA alkyltransferase (AGT) and paradoxically protect cells from the biological effects of DNA alkylation damage, despite lacking the reactive cysteine and alkyltransferase activity of AGT. Here we determine Schizosaccharomyces pombe ATL structures without and with damaged DNA containing the endogenous lesion O(6)-methylguanine or cigarette-smoke-derived O(6)-4-(3-pyridyl)-4-oxobutylguanine. These results reveal non-enzymatic DNA nucleotide flipping plus increased DNA distortion and binding pocket size compared to AGT. Our analysis of lesion-binding site conservation identifies new ATLs in sea anemone and ancestral archaea, indicating that ATL interactions are ancestral to present-day repair pathways in all domains of life. Genetic connections to mammalian XPG (also known as ERCC5) and ERCC1 in S. pombe homologues Rad13 and Swi10 and biochemical interactions with Escherichia coli UvrA and UvrC combined with structural results reveal that ATLs sculpt alkylated DNA to create a genetic and structural intersection of base damage processing with nucleotide excision repair.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2729916/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2729916/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tubbs, Julie L -- Latypov, Vitaly -- Kanugula, Sreenivas -- Butt, Amna -- Melikishvili, Manana -- Kraehenbuehl, Rolf -- Fleck, Oliver -- Marriott, Andrew -- Watson, Amanda J -- Verbeek, Barbara -- McGown, Gail -- Thorncroft, Mary -- Santibanez-Koref, Mauro F -- Millington, Christopher -- Arvai, Andrew S -- Kroeger, Matthew D -- Peterson, Lisa A -- Williams, David M -- Fried, Michael G -- Margison, Geoffrey P -- Pegg, Anthony E -- Tainer, John A -- CA018137/CA/NCI NIH HHS/ -- CA097209/CA/NCI NIH HHS/ -- CA59887/CA/NCI NIH HHS/ -- GM070662/GM/NIGMS NIH HHS/ -- R01 CA059887/CA/NCI NIH HHS/ -- R01 CA059887-12/CA/NCI NIH HHS/ -- R01 CA059887-13/CA/NCI NIH HHS/ -- R01 GM070662/GM/NIGMS NIH HHS/ -- R01 GM070662-01/GM/NIGMS NIH HHS/ -- R01 GM070662-02/GM/NIGMS NIH HHS/ -- R01 GM070662-03/GM/NIGMS NIH HHS/ -- R01 GM070662-04/GM/NIGMS NIH HHS/ -- R01 GM070662-05/GM/NIGMS NIH HHS/ -- R01 GM070662-06/GM/NIGMS NIH HHS/ -- Cancer Research UK/United Kingdom -- England -- Nature. 2009 Jun 11;459(7248):808-13. doi: 10.1038/nature08076.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Skaggs Institute for Chemical Biology and Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19516334" target="_blank"〉PubMed〈/a〉
    Keywords: Alkyl and Aryl Transferases/*chemistry/*metabolism ; Alkylation ; Binding Sites ; Crystallography, X-Ray ; DNA/chemistry/metabolism ; *DNA Damage ; *DNA Repair ; Guanine/analogs & derivatives/chemistry/metabolism ; Humans ; Models, Molecular ; Protein Binding ; Protein Conformation
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    Structural biology: DNA binding shapes up (2009)
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    Publication Date: 2009-10-30
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tullius, Tom -- England -- Nature. 2009 Oct 29;461(7268):1225-6. doi: 10.1038/4611225a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19865161" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; DNA/*chemistry/genetics/*metabolism ; DNA-Binding Proteins/chemistry/*metabolism ; Humans ; *Nucleic Acid Conformation ; Protein Binding
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    Dynamic activation of an allosteric regulatory protein (2009)
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    Publication Date: 2009-11-20
    Description: Allosteric regulation is used as a very efficient mechanism to control protein activity in most biological processes, including signal transduction, metabolism, catalysis and gene regulation. Allosteric proteins can exist in several conformational states with distinct binding or enzymatic activity. Effectors are considered to function in a purely structural manner by selectively stabilizing a specific conformational state, thereby regulating protein activity. Here we show that allosteric proteins can be regulated predominantly by changes in their structural dynamics. We have used NMR spectroscopy and isothermal titration calorimetry to characterize cyclic AMP (cAMP) binding to the catabolite activator protein (CAP), a transcriptional activator that has been a prototype for understanding effector-mediated allosteric control of protein activity. cAMP switches CAP from the 'off' state (inactive), which binds DNA weakly and non-specifically, to the 'on' state (active), which binds DNA strongly and specifically. In contrast, cAMP binding to a single CAP mutant, CAP-S62F, fails to elicit the active conformation; yet, cAMP binding to CAP-S62F strongly activates the protein for DNA binding. NMR and thermodynamic analyses show that despite the fact that CAP-S62F-cAMP(2) adopts the inactive conformation, its strong binding to DNA is driven by a large conformational entropy originating in enhanced protein motions induced by DNA binding. The results provide strong evidence that changes in protein motions may activate allosteric proteins that are otherwise structurally inactive.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tzeng, Shiou-Ru -- Kalodimos, Charalampos G -- England -- Nature. 2009 Nov 19;462(7271):368-72. doi: 10.1038/nature08560.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry & Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19924217" target="_blank"〉PubMed〈/a〉
    Keywords: Cyclic AMP/chemistry/metabolism ; Cyclic AMP Receptor Protein/chemistry/*metabolism ; DNA/metabolism ; *Energy Metabolism ; Escherichia coli/*metabolism ; Escherichia coli Proteins/chemistry/*metabolism ; Models, Molecular ; Protein Binding ; Protein Structure, Tertiary
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    Structure of the outer membrane complex of a type IV secretion system (2009)
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    Publication Date: 2009-12-01
    Description: Type IV secretion systems are secretion nanomachines spanning the two membranes of Gram-negative bacteria. Three proteins, VirB7, VirB9 and VirB10, assemble into a 1.05 megadalton (MDa) core spanning the inner and outer membranes. This core consists of 14 copies of each of the proteins and forms two layers, the I and O layers, inserting in the inner and outer membrane, respectively. Here we present the crystal structure of a approximately 0.6 MDa outer-membrane complex containing the entire O layer. This structure is the largest determined for an outer-membrane channel and is unprecedented in being composed of three proteins. Unexpectedly, this structure identifies VirB10 as the outer-membrane channel with a unique hydrophobic double-helical transmembrane region. This structure establishes VirB10 as the only known protein crossing both membranes of Gram-negative bacteria. Comparison of the cryo-electron microscopy (cryo-EM) and crystallographic structures points to conformational changes regulating channel opening and closing.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797999/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797999/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chandran, Vidya -- Fronzes, Remi -- Duquerroy, Stephane -- Cronin, Nora -- Navaza, Jorge -- Waksman, Gabriel -- 082227/Wellcome Trust/United Kingdom -- England -- Nature. 2009 Dec 24;462(7276):1011-5. doi: 10.1038/nature08588. Epub 2009 Nov 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Structural and Molecular Biology, University College London and Birkbeck College, Malet Street, London WC1E 7HX, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19946264" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Outer Membrane Proteins/*chemistry/isolation & purification ; Gram-Negative Bacteria/*chemistry/*physiology ; *Models, Molecular ; Protein Binding ; Protein Structure, Quaternary
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    Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers (2009)
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    Publication Date: 2009-02-27
    Description: A pathological hallmark of Alzheimer's disease is an accumulation of insoluble plaque containing the amyloid-beta peptide of 40-42 amino acid residues. Prefibrillar, soluble oligomers of amyloid-beta have been recognized to be early and key intermediates in Alzheimer's-disease-related synaptic dysfunction. At nanomolar concentrations, soluble amyloid-beta oligomers block hippocampal long-term potentiation, cause dendritic spine retraction from pyramidal cells and impair rodent spatial memory. Soluble amyloid-beta oligomers have been prepared from chemical syntheses, transfected cell culture supernatants, transgenic mouse brain and human Alzheimer's disease brain. Together, these data imply a high-affinity cell-surface receptor for soluble amyloid-beta oligomers on neurons-one that is central to the pathophysiological process in Alzheimer's disease. Here we identify the cellular prion protein (PrP(C)) as an amyloid-beta-oligomer receptor by expression cloning. Amyloid-beta oligomers bind with nanomolar affinity to PrP(C), but the interaction does not require the infectious PrP(Sc) conformation. Synaptic responsiveness in hippocampal slices from young adult PrP null mice is normal, but the amyloid-beta oligomer blockade of long-term potentiation is absent. Anti-PrP antibodies prevent amyloid-beta-oligomer binding to PrP(C) and rescue synaptic plasticity in hippocampal slices from oligomeric amyloid-beta. Thus, PrP(C) is a mediator of amyloid-beta-oligomer-induced synaptic dysfunction, and PrP(C)-specific pharmaceuticals may have therapeutic potential for Alzheimer's disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748841/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748841/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lauren, Juha -- Gimbel, David A -- Nygaard, Haakon B -- Gilbert, John W -- Strittmatter, Stephen M -- 5T32GN07205/PHS HHS/ -- P30 DA018343/DA/NIDA NIH HHS/ -- R01 NS039962/NS/NINDS NIH HHS/ -- R01 NS039962-09/NS/NINDS NIH HHS/ -- R01 NS042304/NS/NINDS NIH HHS/ -- R01 NS042304-08/NS/NINDS NIH HHS/ -- R37 NS033020/NS/NINDS NIH HHS/ -- R37 NS033020-17/NS/NINDS NIH HHS/ -- England -- Nature. 2009 Feb 26;457(7233):1128-32. doi: 10.1038/nature07761.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cellular Neuroscience, Neurodegeneration and Repair Program, Yale University School of Medicine, New Haven, Connecticut 06536, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19242475" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/metabolism/pathology/physiopathology ; Amyloid Precursor Protein Secretases/metabolism ; Amyloid beta-Peptides/*chemistry/*metabolism ; Amyloidosis/metabolism ; Animals ; COS Cells ; Cercopithecus aethiops ; Hippocampus/cytology/metabolism ; Humans ; Long-Term Potentiation/physiology ; Mice ; Mice, Inbred C57BL ; *Neuronal Plasticity ; Neurons/metabolism ; Peptide Fragments/*chemistry/*metabolism ; Prions/genetics/*metabolism ; Protein Binding ; *Protein Multimerization ; Receptors, Cell Surface/genetics/metabolism ; Synapses/*metabolism/*pathology
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    Cell biology: How to combat stress (2009)
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    Publication Date: 2009-02-06
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nicchitta, Christopher V -- England -- Nature. 2009 Feb 5;457(7230):668-9. doi: 10.1038/457668a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19194438" target="_blank"〉PubMed〈/a〉
    Keywords: Basic-Leucine Zipper Transcription Factors/*genetics ; Crystallography, X-Ray ; Endoplasmic Reticulum/*metabolism ; Membrane Glycoproteins/chemistry/*metabolism ; Protein Biosynthesis ; Protein-Serine-Threonine Kinases/chemistry/*metabolism ; RNA, Fungal/genetics/metabolism ; RNA, Messenger/genetics/*metabolism ; Repressor Proteins/*genetics ; Saccharomyces cerevisiae/*cytology/*genetics ; Saccharomyces cerevisiae Proteins/chemistry/*genetics/*metabolism ; *Stress, Physiological/genetics
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    Key protein-design papers challenged (2009)
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    Publication Date: 2009-10-16
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hayden, Erika Check -- England -- Nature. 2009 Oct 15;461(7266):859. doi: 10.1038/461859a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19829341" target="_blank"〉PubMed〈/a〉
    Keywords: Algorithms ; Computational Biology/*standards ; *Computer Simulation ; Drug Design ; Ligands ; Protein Binding ; *Protein Stability ; Reproducibility of Results ; Research Personnel/ethics/standards ; *Retraction of Publication as Topic ; Scientific Misconduct ; *Substrate Specificity
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    APP binds DR6 to trigger axon pruning and neuron death via distinct caspases (2009)
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    Publication Date: 2009-02-20
    Description: Naturally occurring axonal pruning and neuronal cell death help to sculpt neuronal connections during development, but their mechanistic basis remains poorly understood. Here we report that beta-amyloid precursor protein (APP) and death receptor 6 (DR6, also known as TNFRSF21) activate a widespread caspase-dependent self-destruction program. DR6 is broadly expressed by developing neurons, and is required for normal cell body death and axonal pruning both in vivo and after trophic-factor deprivation in vitro. Unlike neuronal cell body apoptosis, which requires caspase 3, we show that axonal degeneration requires caspase 6, which is activated in a punctate pattern that parallels the pattern of axonal fragmentation. DR6 is activated locally by an inactive surface ligand(s) that is released in an active form after trophic-factor deprivation, and we identify APP as a DR6 ligand. Trophic-factor deprivation triggers the shedding of surface APP in a beta-secretase (BACE)-dependent manner. Loss- and gain-of-function studies support a model in which a cleaved amino-terminal fragment of APP (N-APP) binds DR6 and triggers degeneration. Genetic support is provided by a common neuromuscular junction phenotype in mutant mice. Our results indicate that APP and DR6 are components of a neuronal self-destruction pathway, and suggest that an extracellular fragment of APP, acting via DR6 and caspase 6, contributes to Alzheimer's disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2677572/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2677572/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nikolaev, Anatoly -- McLaughlin, Todd -- O'Leary, Dennis D M -- Tessier-Lavigne, Marc -- R01 AG025970/AG/NIA NIH HHS/ -- R01 EY007025/EY/NEI NIH HHS/ -- R01 EY007025-24/EY/NEI NIH HHS/ -- R01 EY07025/EY/NEI NIH HHS/ -- England -- Nature. 2009 Feb 19;457(7232):981-9. doi: 10.1038/nature07767.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Research, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19225519" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/metabolism ; Amyloid beta-Protein Precursor/chemistry/*metabolism ; Animals ; Axons/*metabolism ; Caspase 3/metabolism ; Caspase 6/*metabolism ; Caspases/*metabolism ; Cell Death ; Ligands ; Mice ; Neurons/*cytology/*metabolism ; Peptide Fragments/chemistry/metabolism ; Protein Binding ; Receptors, Tumor Necrosis Factor/*metabolism ; Signal Transduction ; bcl-2-Associated X Protein/genetics/metabolism
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    A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome (2009)
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    Publication Date: 2009-06-02
    Description: Diverse histone modifications are catalysed and recognized by various specific proteins, establishing unique modification patterns that act as transcription signals. In particular, histone H3 trimethylation at lysine 36 (H3K36me3) is associated with actively transcribed regions and has been proposed to provide landmarks for continuing transcription; however, the control mechanisms and functions of H3K36me3 in higher eukaryotes are unknown. Here we show that the H3K36me3-specific histone methyltransferase (HMTase) Wolf-Hirschhorn syndrome candidate 1 (WHSC1, also known as NSD2 or MMSET) functions in transcriptional regulation together with developmental transcription factors whose defects overlap with the human disease Wolf-Hirschhorn syndrome (WHS). We found that mouse Whsc1, one of five putative Set2 homologues, governed H3K36me3 along euchromatin by associating with the cell-type-specific transcription factors Sall1, Sall4 and Nanog in embryonic stem cells, and Nkx2-5 in embryonic hearts, regulating the expression of their target genes. Whsc1-deficient mice showed growth retardation and various WHS-like midline defects, including congenital cardiovascular anomalies. The effects of Whsc1 haploinsufficiency were increased in Nkx2-5 heterozygous mutant hearts, indicating their functional link. We propose that WHSC1 functions together with developmental transcription factors to prevent the inappropriate transcription that can lead to various pathophysiologies.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nimura, Keisuke -- Ura, Kiyoe -- Shiratori, Hidetaka -- Ikawa, Masato -- Okabe, Masaru -- Schwartz, Robert J -- Kaneda, Yasufumi -- England -- Nature. 2009 Jul 9;460(7252):287-91. doi: 10.1038/nature08086. Epub 2009 May 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Gene Therapy Science, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19483677" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; DNA-Binding Proteins/metabolism ; Gene Expression Regulation ; Histone-Lysine N-Methyltransferase/deficiency/genetics/*metabolism ; Histones/*metabolism ; Homeodomain Proteins/genetics/*metabolism ; Lysine/metabolism ; Methylation ; Mice ; Mice, Inbred C57BL ; Protein Binding ; Repressor Proteins/metabolism ; Transcription Factors/genetics/*metabolism ; Transcription, Genetic ; Wolf-Hirschhorn Syndrome/*metabolism
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    ErbB2 resembles an autoinhibited invertebrate epidermal growth factor receptor (2009)
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    Publication Date: 2009-09-01
    Description: The orphan receptor tyrosine kinase ErbB2 (also known as HER2 or Neu) transforms cells when overexpressed, and it is an important therapeutic target in human cancer. Structural studies have suggested that the oncogenic (and ligand-independent) signalling properties of ErbB2 result from the absence of a key intramolecular 'tether' in the extracellular region that autoinhibits other human ErbB receptors, including the epidermal growth factor (EGF) receptor. Although ErbB2 is unique among the four human ErbB receptors, here we show that it is the closest structural relative of the single EGF receptor family member in Drosophila melanogaster (dEGFR). Genetic and biochemical data show that dEGFR is tightly regulated by growth factor ligands, yet a crystal structure shows that it, too, lacks the intramolecular tether seen in human EGFR, ErbB3 and ErbB4. Instead, a distinct set of autoinhibitory interdomain interactions hold unliganded dEGFR in an inactive state. All of these interactions are maintained (and even extended) in ErbB2, arguing against the suggestion that ErbB2 lacks autoinhibition. We therefore suggest that normal and pathogenic ErbB2 signalling may be regulated by ligands in the same way as dEGFR. Our findings have important implications for ErbB2 regulation in human cancer, and for developing therapeutic approaches that target novel aspects of this orphan receptor.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2762480/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2762480/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Alvarado, Diego -- Klein, Daryl E -- Lemmon, Mark A -- R01 CA079992/CA/NCI NIH HHS/ -- R01 CA079992-09/CA/NCI NIH HHS/ -- R01 CA079992-10/CA/NCI NIH HHS/ -- R01 CA125432/CA/NCI NIH HHS/ -- R01 CA125432-01A1/CA/NCI NIH HHS/ -- R01 CA125432-02/CA/NCI NIH HHS/ -- R01 CA125432-03/CA/NCI NIH HHS/ -- England -- Nature. 2009 Sep 10;461(7261):287-91. doi: 10.1038/nature08297. Epub 2009 Aug 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 809C Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19718021" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Crystallography, X-Ray ; Drosophila Proteins/*antagonists & inhibitors/chemistry/genetics/*metabolism ; Drosophila melanogaster/chemistry/*metabolism ; Enzyme Activation ; Humans ; Ligands ; Models, Molecular ; Protein Structure, Tertiary ; Receptor, Epidermal Growth Factor/*antagonists & ; inhibitors/chemistry/genetics/*metabolism ; Receptor, ErbB-2/antagonists & inhibitors/*chemistry/*metabolism ; Receptors, Invertebrate Peptide/*antagonists & ; inhibitors/chemistry/genetics/*metabolism ; Scattering, Small Angle ; Solubility ; X-Ray Diffraction
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    Structure of a prokaryotic virtual proton pump at 3.2 A resolution (2009)
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    Details
    Publication Date: 2009-07-07
    Description: To reach the mammalian gut, enteric bacteria must pass through the stomach. Many such organisms survive exposure to the harsh gastric environment (pH 1.5-4) by mounting extreme acid-resistance responses, one of which, the arginine-dependent system of Escherichia coli, has been studied at levels of cellular physiology, molecular genetics and protein biochemistry. This multiprotein system keeps the cytoplasm above pH 5 during acid challenge by continually pumping protons out of the cell using the free energy of arginine decarboxylation. At the heart of the process is a 'virtual proton pump' in the inner membrane, called AdiC, that imports L-arginine from the gastric juice and exports its decarboxylation product agmatine. AdiC belongs to the APC superfamily of membrane proteins, which transports amino acids, polyamines and organic cations in a multitude of biological roles, including delivery of arginine for nitric oxide synthesis, facilitation of insulin release from pancreatic beta-cells, and, when inappropriately overexpressed, provisioning of certain fast-growing neoplastic cells with amino acids. High-resolution structures and detailed transport mechanisms of APC transporters are currently unknown. Here we describe a crystal structure of AdiC at 3.2 A resolution. The protein is captured in an outward-open, substrate-free conformation with transmembrane architecture remarkably similar to that seen in four other families of apparently unrelated transport proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2745212/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2745212/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fang, Yiling -- Jayaram, Hariharan -- Shane, Tania -- Kolmakova-Partensky, Ludmila -- Wu, Fang -- Williams, Carole -- Xiong, Yong -- Miller, Christopher -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 GM031768/GM/NIGMS NIH HHS/ -- R01 GM031768-26/GM/NIGMS NIH HHS/ -- R01 GM089688/GM/NIGMS NIH HHS/ -- T32 NS 07292/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Aug 20;460(7258):1040-3. doi: 10.1038/nature08201. Epub 2009 Jul 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, Massachusetts 02454, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19578361" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Amino Acid Transport Systems/*chemistry/metabolism ; Antiporters/*chemistry/metabolism ; Bacterial Proteins/*chemistry ; Crystallography, X-Ray ; Escherichia coli/*chemistry ; Escherichia coli Proteins/*chemistry/metabolism ; Models, Molecular ; Molecular Sequence Data ; Multigene Family ; Protein Conformation ; Salmonella typhi/*chemistry ; Structural Homology, Protein
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    Structural basis of inter-protein electron transfer for nitrite reduction in denitrification (2009)
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    Publication Date: 2009-11-06
    Description: Recent earth science studies have pointed out that massive acceleration of the global nitrogen cycle by anthropogenic addition of bio-available nitrogen has led to a host of environmental problems. Nitrous oxide (N(2)O) is a greenhouse gas that is an intermediate during the biological process known as denitrification. Copper-containing nitrite reductase (CuNIR) is a key enzyme in the process; it produces a precursor for N(2)O by catalysing the one-electron reduction of nitrite (NO2-) to nitric oxide (NO). The reduction step is performed by an efficient electron-transfer reaction with a redox-partner protein. However, details of the mechanism during the electron-transfer reaction are still unknown. Here we show the high-resolution crystal structure of the electron-transfer complex for CuNIR with its cognate cytochrome c as the electron donor. The hydrophobic electron-transfer path is formed at the docking interface by desolvation owing to close contact between the two proteins. Structural analysis of the interface highlights an essential role for the loop region with a hydrophobic patch for protein-protein recognition; it also shows how interface construction allows the variation in atomic components to achieve diverse biological electron transfers.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nojiri, Masaki -- Koteishi, Hiroyasu -- Nakagami, Takuya -- Kobayashi, Kazuo -- Inoue, Tsuyoshi -- Yamaguchi, Kazuya -- Suzuki, Shinnichiro -- England -- Nature. 2009 Nov 5;462(7269):117-20. doi: 10.1038/nature08507.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan. nojiri@ch.wani.osaka-u.ac.jp〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19890332" target="_blank"〉PubMed〈/a〉
    Keywords: Achromobacter denitrificans/*enzymology ; Crystallography, X-Ray ; Cytochromes c/chemistry/metabolism ; Electron Transport ; Hydrophobic and Hydrophilic Interactions ; Models, Molecular ; Nitric Oxide/metabolism ; Nitrite Reductases/*chemistry/*metabolism ; Nitrites/metabolism ; Nitrous Oxide/metabolism ; Protein Conformation ; Structure-Activity Relationship
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    Transmembrane passage of hydrophobic compounds through a protein channel wall (2009)
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    Publication Date: 2009-02-03
    Description: Membrane proteins that transport hydrophobic compounds have important roles in multi-drug resistance and can cause a number of diseases, underscoring the importance of protein-mediated transport of hydrophobic compounds. Hydrophobic compounds readily partition into regular membrane lipid bilayers, and their transport through an aqueous protein channel is energetically unfavourable. Alternative transport models involving acquisition from the lipid bilayer by lateral diffusion have been proposed for hydrophobic substrates. So far, all transport proteins for which a lateral diffusion mechanism has been proposed function as efflux pumps. Here we present the first example of a lateral diffusion mechanism for the uptake of hydrophobic substrates by the Escherichia coli outer membrane long-chain fatty acid transporter FadL. A FadL mutant in which a lateral opening in the barrel wall is constricted, but which is otherwise structurally identical to wild-type FadL, does not transport substrates. A crystal structure of FadL from Pseudomonas aeruginosa shows that the opening in the wall of the beta-barrel is conserved and delineates a long, hydrophobic tunnel that could mediate substrate passage from the extracellular environment, through the polar lipopolysaccharide layer and, by means of the lateral opening in the barrel wall, into the lipid bilayer from where the substrate can diffuse into the periplasm. Because FadL homologues are found in pathogenic and biodegrading bacteria, our results have implications for combating bacterial infections and bioremediating xenobiotics in the environment.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2658730/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2658730/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hearn, Elizabeth M -- Patel, Dimki R -- Lepore, Bryan W -- Indic, Mridhu -- van den Berg, Bert -- 1R01GM074824/GM/NIGMS NIH HHS/ -- F32 GM079820-01/GM/NIGMS NIH HHS/ -- F32 GM079820-02/GM/NIGMS NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 GM074824/GM/NIGMS NIH HHS/ -- R01 GM074824-01/GM/NIGMS NIH HHS/ -- R01 GM074824-02/GM/NIGMS NIH HHS/ -- R01 GM074824-03/GM/NIGMS NIH HHS/ -- R01 GM074824-04/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Mar 19;458(7236):367-70. doi: 10.1038/nature07678. Epub 2009 Feb 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19182779" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Outer Membrane Proteins/*chemistry/genetics/*metabolism ; Cloning, Molecular ; Crystallography, X-Ray ; Diffusion ; Escherichia coli/*chemistry/genetics ; Escherichia coli Proteins/*chemistry/genetics/*metabolism ; Fatty Acid Transport Proteins/*chemistry/genetics/*metabolism ; Hydrophobic and Hydrophilic Interactions ; Lipid Bilayers/metabolism ; Models, Molecular ; Pseudomonas aeruginosa/*chemistry/genetics
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    Characterization of two classes of small molecule inhibitors of Arp2/3 complex (2009)
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    Publication Date: 2009-08-04
    Description: Polymerization of actin filaments directed by the actin-related protein (Arp)2/3 complex supports many types of cellular movements. However, questions remain regarding the relative contributions of Arp2/3 complex versus other mechanisms of actin filament nucleation to processes such as path finding by neuronal growth cones; this is because of the lack of simple methods to inhibit Arp2/3 complex reversibly in living cells. Here we describe two classes of small molecules that bind to different sites on the Arp2/3 complex and inhibit its ability to nucleate actin filaments. CK-0944636 binds between Arp2 and Arp3, where it appears to block movement of Arp2 and Arp3 into their active conformation. CK-0993548 inserts into the hydrophobic core of Arp3 and alters its conformation. Both classes of compounds inhibit formation of actin filament comet tails by Listeria and podosomes by monocytes. Two inhibitors with different mechanisms of action provide a powerful approach for studying the Arp2/3 complex in living cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2780427/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2780427/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nolen, B J -- Tomasevic, N -- Russell, A -- Pierce, D W -- Jia, Z -- McCormick, C D -- Hartman, J -- Sakowicz, R -- Pollard, T D -- F32 GM074374-02/GM/NIGMS NIH HHS/ -- GM-066311/GM/NIGMS NIH HHS/ -- GM074374-02/GM/NIGMS NIH HHS/ -- P01 GM066311/GM/NIGMS NIH HHS/ -- P01 GM066311-01A1/GM/NIGMS NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- England -- Nature. 2009 Aug 20;460(7258):1031-4. doi: 10.1038/nature08231. Epub 2009 Aug 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19648907" target="_blank"〉PubMed〈/a〉
    Keywords: Actin Cytoskeleton/drug effects/metabolism ; Actin-Related Protein 2/antagonists & inhibitors/chemistry/metabolism ; Actin-Related Protein 2-3 Complex/*antagonists & inhibitors/chemistry/metabolism ; Actin-Related Protein 3/antagonists & inhibitors/chemistry/metabolism ; Actins/chemistry/metabolism ; Animals ; Biopolymers/chemistry/metabolism ; Cattle ; Cell Line ; Crystallography, X-Ray ; Humans ; Hydrophobic and Hydrophilic Interactions ; Indoles/classification/metabolism/pharmacology ; Listeria/physiology ; Models, Molecular ; Monocytes/immunology ; Protein Conformation/drug effects ; Schizosaccharomyces ; Thiazoles/chemistry/classification/metabolism/pharmacology ; Thiophenes/classification/metabolism/pharmacology
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    Structural biology: Highly charged meetings (2009)
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    Publication Date: 2009-11-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Anthony G -- England -- Nature. 2009 Nov 26;462(7272):420-1. doi: 10.1038/462420a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19940907" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Hydrogen Bonding ; Hydrophobic and Hydrophilic Interactions ; Lipid Bilayers/*chemistry/*metabolism ; Models, Molecular ; Molecular Dynamics Simulation ; Neutron Diffraction ; Potassium Channels, Voltage-Gated/*chemistry/*metabolism ; Protein Structure, Tertiary ; Static Electricity
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    Structural biology: A channel with a twist (2009)
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    Publication Date: 2009-09-04
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vasquez, Valeria -- Perozo, Eduardo -- England -- Nature. 2009 Sep 3;461(7260):47-9. doi: 10.1038/461047a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19727188" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/*metabolism ; Crystallography, X-Ray ; Ion Channel Gating/*physiology ; Ion Channels/*chemistry/*metabolism ; Models, Biological ; Models, Molecular ; Mycobacterium tuberculosis/chemistry ; Pressure ; Protein Structure, Quaternary ; Staphylococcus aureus/*chemistry
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    Pyrrolysyl-tRNA synthetase-tRNA(Pyl) structure reveals the molecular basis of orthogonality (2009)
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    Publication Date: 2009-01-02
    Description: Pyrrolysine (Pyl), the 22nd natural amino acid, is genetically encoded by UAG and inserted into proteins by the unique suppressor tRNA(Pyl) (ref. 1). The Methanosarcinaceae produce Pyl and express Pyl-containing methyltransferases that allow growth on methylamines. Homologous methyltransferases and the Pyl biosynthetic and coding machinery are also found in two bacterial species. Pyl coding is maintained by pyrrolysyl-tRNA synthetase (PylRS), which catalyses the formation of Pyl-tRNA(Pyl) (refs 4, 5). Pyl is not a recent addition to the genetic code. PylRS was already present in the last universal common ancestor; it then persisted in organisms that utilize methylamines as energy sources. Recent protein engineering efforts added non-canonical amino acids to the genetic code. This technology relies on the directed evolution of an 'orthogonal' tRNA synthetase-tRNA pair in which an engineered aminoacyl-tRNA synthetase (aaRS) specifically and exclusively acylates the orthogonal tRNA with a non-canonical amino acid. For Pyl the natural evolutionary process developed such a system some 3 billion years ago. When transformed into Escherichia coli, Methanosarcina barkeri PylRS and tRNA(Pyl) function as an orthogonal pair in vivo. Here we show that Desulfitobacterium hafniense PylRS-tRNA(Pyl) is an orthogonal pair in vitro and in vivo, and present the crystal structure of this orthogonal pair. The ancient emergence of PylRS-tRNA(Pyl) allowed the evolution of unique structural features in both the protein and the tRNA. These structural elements manifest an intricate, specialized aaRS-tRNA interaction surface that is highly distinct from those observed in any other known aaRS-tRNA complex; it is this general property that underlies the molecular basis of orthogonality.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2648862/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2648862/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nozawa, Kayo -- O'Donoghue, Patrick -- Gundllapalli, Sarath -- Araiso, Yuhei -- Ishitani, Ryuichiro -- Umehara, Takuya -- Soll, Dieter -- Nureki, Osamu -- R01 GM022854/GM/NIGMS NIH HHS/ -- R01 GM022854-33/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Feb 26;457(7233):1163-7. doi: 10.1038/nature07611. Epub 2008 Dec 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, B34 4259 Nagatsuta-cho, Midori-ku, Yokohama-shi, Kanagawa 226-8501, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19118381" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acyl-tRNA Synthetases/*chemistry/genetics/*metabolism ; Aminoacylation ; Crystallography, X-Ray ; Desulfitobacterium/*enzymology/genetics ; Escherichia coli/genetics ; Lysine/*analogs & derivatives/biosynthesis/genetics/metabolism ; Methanosarcina barkeri/enzymology/genetics ; Models, Molecular ; RNA, Transfer, Amino Acid-Specific/genetics/metabolism ; Structural Homology, Protein
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    Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates (2009)
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    Publication Date: 2009-02-20
    Description: The complement system is an essential component of the innate and acquired immune system, and consists of a series of proteolytic cascades that are initiated by the presence of microorganisms. In health, activation of complement is precisely controlled through membrane-bound and soluble plasma-regulatory proteins including complement factor H (fH; ref. 2), a 155 kDa protein composed of 20 domains (termed complement control protein repeats). Many pathogens have evolved the ability to avoid immune-killing by recruiting host complement regulators and several pathogens have adapted to avoid complement-mediated killing by sequestering fH to their surface. Here we present the structure of a complement regulator in complex with its pathogen surface-protein ligand. This reveals how the important human pathogen Neisseria meningitidis subverts immune responses by mimicking the host, using protein instead of charged-carbohydrate chemistry to recruit the host complement regulator, fH. The structure also indicates the molecular basis of the host-specificity of the interaction between fH and the meningococcus, and informs attempts to develop novel therapeutics and vaccines.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670278/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670278/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schneider, Muriel C -- Prosser, Beverly E -- Caesar, Joseph J E -- Kugelberg, Elisabeth -- Li, Su -- Zhang, Qian -- Quoraishi, Sadik -- Lovett, Janet E -- Deane, Janet E -- Sim, Robert B -- Roversi, Pietro -- Johnson, Steven -- Tang, Christoph M -- Lea, Susan M -- 083599/Wellcome Trust/United Kingdom -- G0400775/Medical Research Council/United Kingdom -- G0400775(71657)/Medical Research Council/United Kingdom -- G0500367/Medical Research Council/United Kingdom -- G0601195/Medical Research Council/United Kingdom -- G0601195(79743)/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2009 Apr 16;458(7240):890-3. doi: 10.1038/nature07769. Epub 2009 Feb 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Molecular Microbiology and Infection, Imperial College, London SW7 2AZ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19225461" target="_blank"〉PubMed〈/a〉
    Keywords: Antigens, Bacterial/*chemistry/*metabolism ; Bacterial Proteins/*chemistry/*metabolism ; Binding Sites ; Carbohydrates/*chemistry ; Complement Factor H/*chemistry/immunology/*metabolism ; Crystallography, X-Ray ; Ligands ; Models, Molecular ; *Molecular Mimicry ; Neisseria meningitidis/chemistry/immunology/*metabolism ; Nuclear Magnetic Resonance, Biomolecular ; Protein Binding ; Protein Conformation ; Structure-Activity Relationship ; Substrate Specificity
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    AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA (2009)
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    Publication Date: 2009-01-23
    Description: Host- and pathogen-associated cytoplasmic double-stranded DNA triggers the activation of a NALP3 (also known as cryopyrin and NLRP3)-independent inflammasome, which activates caspase-1 leading to maturation of pro-interleukin-1beta and inflammation. The nature of the cytoplasmic-DNA-sensing inflammasome is currently unknown. Here we show that AIM2 (absent in melanoma 2), an interferon-inducible HIN-200 family member that contains an amino-terminal pyrin domain and a carboxy-terminal oligonucleotide/oligosaccharide-binding domain, senses cytoplasmic DNA by means of its oligonucleotide/oligosaccharide-binding domain and interacts with ASC (apoptosis-associated speck-like protein containing a CARD) through its pyrin domain to activate caspase-1. The interaction of AIM2 with ASC also leads to the formation of the ASC pyroptosome, which induces pyroptotic cell death in cells containing caspase-1. Knockdown of AIM2 by short interfering RNA reduced inflammasome/pyroptosome activation by cytoplasmic DNA in human and mouse macrophages, whereas stable expression of AIM2 in the non-responsive human embryonic kidney 293T cell line conferred responsiveness to cytoplasmic DNA. Our results show that cytoplasmic DNA triggers formation of the AIM2 inflammasome by inducing AIM2 oligomerization. This study identifies AIM2 as an important inflammasome component that senses potentially dangerous cytoplasmic DNA, leading to activation of the ASC pyroptosome and caspase-1.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2862225/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2862225/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fernandes-Alnemri, Teresa -- Yu, Je-Wook -- Datta, Pinaki -- Wu, Jianghong -- Alnemri, Emad S -- AG14357/AG/NIA NIH HHS/ -- AR055398/AR/NIAMS NIH HHS/ -- R01 AG014357/AG/NIA NIH HHS/ -- R01 AG014357-11/AG/NIA NIH HHS/ -- R01 AR055398/AR/NIAMS NIH HHS/ -- R01 AR055398-11A2/AR/NIAMS NIH HHS/ -- England -- Nature. 2009 Mar 26;458(7237):509-13. doi: 10.1038/nature07710. Epub 2009 Jan 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, Center for Apoptosis Research, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19158676" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis Regulatory Proteins ; Caspase 1/metabolism ; Cell Death ; Cell Line ; Cytoplasm/*genetics ; Cytoskeletal Proteins/metabolism ; DNA/immunology/*metabolism ; DNA-Binding Proteins ; Enzyme Activation ; Humans ; Inflammation/*metabolism/*pathology ; Mice ; Nuclear Proteins/chemistry/deficiency/genetics/*metabolism ; Protein Binding
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    An unusual carbon-carbon bond cleavage reaction during phosphinothricin biosynthesis (2009)
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    Publication Date: 2009-06-12
    Description: Natural products containing phosphorus-carbon bonds have found widespread use in medicine and agriculture. One such compound, phosphinothricin tripeptide, contains the unusual amino acid phosphinothricin attached to two alanine residues. Synthetic phosphinothricin (glufosinate) is a component of two top-selling herbicides (Basta and Liberty), and is widely used with resistant transgenic crops including corn, cotton and canola. Recent genetic and biochemical studies showed that during phosphinothricin tripeptide biosynthesis 2-hydroxyethylphosphonate (HEP) is converted to hydroxymethylphosphonate (HMP). Here we report the in vitro reconstitution of this unprecedented C(sp(3))-C(sp(3)) bond cleavage reaction and X-ray crystal structures of the enzyme. The protein is a mononuclear non-haem iron(ii)-dependent dioxygenase that converts HEP to HMP and formate. In contrast to most other members of this family, the oxidative consumption of HEP does not require additional cofactors or the input of exogenous electrons. The current study expands the scope of reactions catalysed by the 2-His-1-carboxylate mononuclear non-haem iron family of enzymes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874955/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874955/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cicchillo, Robert M -- Zhang, Houjin -- Blodgett, Joshua A V -- Whitteck, John T -- Li, Gongyong -- Nair, Satish K -- van der Donk, Wilfred A -- Metcalf, William W -- P01 GM077596/GM/NIGMS NIH HHS/ -- P01 GM077596-03/GM/NIGMS NIH HHS/ -- R01 GM059334/GM/NIGMS NIH HHS/ -- R01 GM059334-09/GM/NIGMS NIH HHS/ -- R01 GM59334/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Jun 11;459(7248):871-4. doi: 10.1038/nature07972.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19516340" target="_blank"〉PubMed〈/a〉
    Keywords: Aminobutyrates/*chemistry/*metabolism ; Biocatalysis ; Crystallography, X-Ray ; Dioxygenases/chemistry/genetics/*metabolism ; Escherichia coli ; Formates/metabolism ; Magnetic Resonance Spectroscopy ; Mass Spectrometry ; Models, Biological ; Models, Molecular ; Molecular Conformation ; Organophosphonates/metabolism
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    Crystal structure of a bacterial homologue of the kidney urea transporter (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-10-30
    Description: Urea is highly concentrated in the mammalian kidney to produce the osmotic gradient necessary for water re-absorption. Free diffusion of urea across cell membranes is slow owing to its high polarity, and specialized urea transporters have evolved to achieve rapid and selective urea permeation. Here we present the 2.3 A structure of a functional urea transporter from the bacterium Desulfovibrio vulgaris. The transporter is a homotrimer, and each subunit contains a continuous membrane-spanning pore formed by the two homologous halves of the protein. The pore contains a constricted selectivity filter that can accommodate several dehydrated urea molecules in single file. Backbone and side-chain oxygen atoms provide continuous coordination of urea as it progresses through the filter, and well-placed alpha-helix dipoles provide further compensation for dehydration energy. These results establish that the urea transporter operates by a channel-like mechanism and reveal the physical and chemical basis of urea selectivity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2871279/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2871279/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Levin, Elena J -- Quick, Matthias -- Zhou, Ming -- GM075026/GM/NIGMS NIH HHS/ -- HL086392/HL/NHLBI NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 DK088057/DK/NIDDK NIH HHS/ -- R01 HL086392/HL/NHLBI NIH HHS/ -- R01 HL086392-04/HL/NHLBI NIH HHS/ -- R01 HL086392-04S1/HL/NHLBI NIH HHS/ -- R01 HL086392-05/HL/NHLBI NIH HHS/ -- T32 HL087745/HL/NHLBI NIH HHS/ -- T32 HL087745-03/HL/NHLBI NIH HHS/ -- T32HL087745/HL/NHLBI NIH HHS/ -- U54 GM075026/GM/NIGMS NIH HHS/ -- U54 GM075026-040007/GM/NIGMS NIH HHS/ -- U54 GM075026-050007/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Dec 10;462(7274):757-61. doi: 10.1038/nature08558. Epub .〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology & Cellular Biophysics, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19865084" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Crystallography, X-Ray ; Desulfovibrio vulgaris/*chemistry ; Humans ; Kidney/*chemistry ; Membrane Transport Proteins/*chemistry/*metabolism ; Models, Molecular ; Oocytes/metabolism ; Protein Folding ; Protein Structure, Quaternary ; Protein Subunits/chemistry/metabolism ; Structure-Activity Relationship ; Urea/metabolism ; Xenopus laevis
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    The origin of the electrostatic perturbation in acetoacetate decarboxylase (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-05-22
    Description: Acetoacetate decarboxylase (AADase) has long been cited as the prototypical example of the marked shifts in the pK(a) values of ionizable groups that can occur in an enzyme active site. In 1966, it was hypothesized that in AADase the origin of the large pK(a) perturbation (-4.5 log units) observed in the nucleophilic Lys 115 results from the proximity of Lys 116, marking the first proposal of microenvironment effects in enzymology. The electrostatic perturbation hypothesis has been demonstrated in a number of enzymes, but never for the enzyme that inspired its conception, owing to the lack of a three-dimensional structure. Here we present the X-ray crystal structures of AADase and of the enamine adduct with the substrate analogue 2,4-pentanedione. Surprisingly, the shift of the pK(a) of Lys 115 is not due to the proximity of Lys 116, the side chain of which is oriented away from the active site. Instead, Lys 116 participates in the structural anchoring of Lys 115 in a long, hydrophobic funnel provided by the novel fold of the enzyme. Thus, AADase perturbs the pK(a) of the nucleophile by means of a desolvation effect by placement of the side chain into the protein core while enforcing the proximity of polar residues, which facilitate decarboxylation through electrostatic and steric effects.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ho, Meng-Chiao -- Menetret, Jean-Francois -- Tsuruta, Hiro -- Allen, Karen N -- England -- Nature. 2009 May 21;459(7245):393-7. doi: 10.1038/nature07938.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts 02118-2394, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19458715" target="_blank"〉PubMed〈/a〉
    Keywords: Biocatalysis ; Carboxy-Lyases/*chemistry ; Catalytic Domain ; Chromobacterium/*enzymology ; Clostridium acetobutylicum/*enzymology ; Crystallography, X-Ray ; Decarboxylation ; Hydrophobic and Hydrophilic Interactions ; Lysine/chemistry/metabolism ; Models, Molecular ; Pentanones/metabolism ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Static Electricity
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    The Fas-FADD death domain complex structure unravels signalling by receptor clustering (2009)
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    Publication Date: 2009-01-02
    Description: The death inducing signalling complex (DISC) formed by Fas receptor, FADD (Fas-associated death domain protein) and caspase 8 is a pivotal trigger of apoptosis. The Fas-FADD DISC represents a receptor platform, which once assembled initiates the induction of programmed cell death. A highly oligomeric network of homotypic protein interactions comprised of the death domains of Fas and FADD is at the centre of DISC formation. Thus, characterizing the mechanistic basis for the Fas-FADD interaction is crucial for understanding DISC signalling but has remained unclear largely because of a lack of structural data. We have successfully formed and isolated the human Fas-FADD death domain complex and report the 2.7 A crystal structure. The complex shows a tetrameric arrangement of four FADD death domains bound to four Fas death domains. We show that an opening of the Fas death domain exposes the FADD binding site and simultaneously generates a Fas-Fas bridge. The result is a regulatory Fas-FADD complex bridge governed by weak protein-protein interactions revealing a model where the complex itself functions as a mechanistic switch. This switch prevents accidental DISC assembly, yet allows for highly processive DISC formation and clustering upon a sufficient stimulus. In addition to depicting a previously unknown mode of death domain interactions, these results further uncover a mechanism for receptor signalling solely by oligomerization and clustering events.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661029/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661029/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Scott, Fiona L -- Stec, Boguslaw -- Pop, Cristina -- Dobaczewska, Malgorzata K -- Lee, JeongEun J -- Monosov, Edward -- Robinson, Howard -- Salvesen, Guy S -- Schwarzenbacher, Robert -- Riedl, Stefan J -- P01 CA069381/CA/NCI NIH HHS/ -- P01 CA069381-130009/CA/NCI NIH HHS/ -- P01CA69381/CA/NCI NIH HHS/ -- P30 CA030199/CA/NCI NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01AA017238/AA/NIAAA NIH HHS/ -- England -- Nature. 2009 Feb 19;457(7232):1019-22. doi: 10.1038/nature07606. Epub 2008 Dec 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Apoptosis and Cell Death Research, The Burnham Institute for Medical Research, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19118384" target="_blank"〉PubMed〈/a〉
    Keywords: Antigens, CD95/*chemistry/*metabolism ; Crystallography, X-Ray ; Death Domain Receptor Signaling Adaptor Proteins/chemistry/metabolism ; Fas-Associated Death Domain Protein/*chemistry/*metabolism ; Humans ; Models, Molecular ; Multiprotein Complexes/chemistry/metabolism ; *Receptor Aggregation ; *Signal Transduction
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    Structure and mechanism of a bacterial light-regulated cyclic nucleotide phosphodiesterase (2009)
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    Publication Date: 2009-06-19
    Description: The ability to respond to light is crucial for most organisms. BLUF is a recently identified photoreceptor protein domain that senses blue light using a FAD chromophore. BLUF domains are present in various proteins from the Bacteria, Euglenozoa and Fungi. Although structures of single-domain BLUF proteins have been determined, none are available for a BLUF protein containing a functional output domain; the mechanism of light activation in this new class of photoreceptors has thus remained poorly understood. Here we report the biochemical, structural and mechanistic characterization of a full-length, active photoreceptor, BlrP1 (also known as KPN_01598), from Klebsiella pneumoniae. BlrP1 consists of a BLUF sensor domain and a phosphodiesterase EAL output domain which hydrolyses cyclic dimeric GMP (c-di-GMP). This ubiquitous second messenger controls motility, biofilm formation, virulence and antibiotic resistance in the Bacteria. Crystal structures of BlrP1 complexed with its substrate and metal ions involved in catalysis or in enzyme inhibition provide a detailed understanding of the mechanism of the EAL-domain c-di-GMP phosphodiesterases. These structures also sketch out a path of light activation of the phosphodiesterase output activity. Photon absorption by the BLUF domain of one subunit of the antiparallel BlrP1 homodimer activates the EAL domain of the second subunit through allosteric communication transmitted through conserved domain-domain interfaces.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Barends, Thomas R M -- Hartmann, Elisabeth -- Griese, Julia J -- Beitlich, Thorsten -- Kirienko, Natalia V -- Ryjenkov, Dmitri A -- Reinstein, Jochen -- Shoeman, Robert L -- Gomelsky, Mark -- Schlichting, Ilme -- England -- Nature. 2009 Jun 18;459(7249):1015-8. doi: 10.1038/nature07966.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute for Medical Research, Department of Biomolecular Mechanisms, Jahnstrasse 29, 69120 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19536266" target="_blank"〉PubMed〈/a〉
    Keywords: 3',5'-Cyclic-GMP Phosphodiesterases/*chemistry/metabolism/*radiation effects ; Allosteric Regulation/radiation effects ; Biocatalysis/radiation effects ; Catalytic Domain ; Crystallography, X-Ray ; Cyclic GMP/analogs & derivatives/metabolism ; Klebsiella pneumoniae/*enzymology ; *Light ; Metals/metabolism ; Models, Molecular ; Phosphorus/metabolism ; Photons ; Photoreceptors, Microbial/*chemistry/metabolism/*radiation effects ; Protein Multimerization ; Protein Structure, Quaternary ; Protein Structure, Tertiary
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    AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC (2009)
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    Publication Date: 2009-01-23
    Description: The innate immune system senses nucleic acids by germline-encoded pattern recognition receptors. RNA is sensed by Toll-like receptor members TLR3, TLR7 and TLR8, or by the RNA helicases RIG-I (also known as DDX58) and MDA-5 (IFIH1). Little is known about sensors for cytoplasmic DNA that trigger antiviral and/or inflammatory responses. The best characterized of these responses involves activation of the TANK-binding kinase (TBK1)-interferon regulatory factor 3 (IRF3) signalling axis to trigger transcriptional induction of type I interferon genes. A second, less well-defined pathway leads to the activation of an 'inflammasome' that, via caspase-1, controls the catalytic cleavage of the pro-forms of the cytokines IL1beta and IL18 (refs 6, 7). Using mouse and human cells, here we identify the PYHIN (pyrin and HIN domain-containing protein) family member absent in melanoma 2 (AIM2) as a receptor for cytosolic DNA, which regulates caspase-1. The HIN200 domain of AIM2 binds to DNA, whereas the pyrin domain (but not that of the other PYHIN family members) associates with the adaptor molecule ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain) to activate both NF-kappaB and caspase-1. Knockdown of Aim2 abrogates caspase-1 activation in response to cytoplasmic double-stranded DNA and the double-stranded DNA vaccinia virus. Collectively, these observations identify AIM2 as a new receptor for cytoplasmic DNA, which forms an inflammasome with the ligand and ASC to activate caspase-1.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726264/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726264/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hornung, Veit -- Ablasser, Andrea -- Charrel-Dennis, Marie -- Bauernfeind, Franz -- Horvath, Gabor -- Caffrey, Daniel R -- Latz, Eicke -- Fitzgerald, Katherine A -- AI-065483/AI/NIAID NIH HHS/ -- AI-067497/AI/NIAID NIH HHS/ -- R01 AI067497/AI/NIAID NIH HHS/ -- R01 AI067497-03/AI/NIAID NIH HHS/ -- R01 AI067497-04/AI/NIAID NIH HHS/ -- R01 AI067497-05/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Mar 26;458(7237):514-8. doi: 10.1038/nature07725. Epub 2009 Jan 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. veit.hornung@uni-bonn.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19158675" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis Regulatory Proteins ; Caspase 1/*metabolism ; Cell Death ; Cell Line ; Cytoskeletal Proteins/genetics/*metabolism ; Cytosol/*metabolism ; DNA/immunology/*metabolism ; DNA-Binding Proteins ; Enzyme Activation ; Humans ; Inflammation/enzymology/*metabolism/pathology ; Mice ; Nuclear Proteins/chemistry/genetics/*metabolism ; Poly dA-dT/immunology ; Protein Binding ; Vaccinia virus/immunology
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    The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex (2009)
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    Publication Date: 2009-03-03
    Description: The lipopolysaccharide (LPS) of Gram negative bacteria is a well-known inducer of the innate immune response. Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules. To understand the ligand specificity and receptor activation mechanism of the TLR4-MD-2-LPS complex we determined its crystal structure. LPS binding induced the formation of an m-shaped receptor multimer composed of two copies of the TLR4-MD-2-LPS complex arranged symmetrically. LPS interacts with a large hydrophobic pocket in MD-2 and directly bridges the two components of the multimer. Five of the six lipid chains of LPS are buried deep inside the pocket and the remaining chain is exposed to the surface of MD-2, forming a hydrophobic interaction with the conserved phenylalanines of TLR4. The F126 loop of MD-2 undergoes localized structural change and supports this core hydrophobic interface by making hydrophilic interactions with TLR4. Comparison with the structures of tetra-acylated antagonists bound to MD-2 indicates that two other lipid chains in LPS displace the phosphorylated glucosamine backbone by approximately 5 A towards the solvent area. This structural shift allows phosphate groups of LPS to contribute to receptor multimerization by forming ionic interactions with a cluster of positively charged residues in TLR4 and MD-2. The TLR4-MD-2-LPS structure illustrates the remarkable versatility of the ligand recognition mechanisms employed by the TLR family, which is essential for defence against diverse microbial infection.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Park, Beom Seok -- Song, Dong Hyun -- Kim, Ho Min -- Choi, Byong-Seok -- Lee, Hayyoung -- Lee, Jie-Oh -- England -- Nature. 2009 Apr 30;458(7242):1191-5. doi: 10.1038/nature07830. Epub 2009 Mar 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, KAIST, Daejeon, 305-701, Korea.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19252480" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Crystallography, X-Ray ; Escherichia coli/chemistry ; Humans ; Hydrophobic and Hydrophilic Interactions ; Lipopolysaccharides/*chemistry/*immunology ; Lymphocyte Antigen 96/*chemistry/*immunology ; Models, Molecular ; Protein Binding ; Protein Multimerization ; Structure-Activity Relationship ; Toll-Like Receptor 4/*chemistry/*immunology
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    Chemical biology: Caught in the activation (2009)
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    Publication Date: 2009-09-26
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Yi -- England -- Nature. 2009 Sep 24;461(7263):484-5. doi: 10.1038/461484a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19779441" target="_blank"〉PubMed〈/a〉
    Keywords: Catalytic Domain ; Crystallography, X-Ray ; Enzyme Activation/drug effects ; Humans ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/pharmacology/therapeutic use ; Protein-Serine-Threonine Kinases/*chemistry/*metabolism
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    Structure of a tetrameric MscL in an expanded intermediate state (2009)
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    Publication Date: 2009-08-25
    Description: The ability of cells to sense and respond to mechanical force underlies diverse processes such as touch and hearing in animals, gravitropism in plants, and bacterial osmoregulation. In bacteria, mechanosensation is mediated by the mechanosensitive channels of large (MscL), small (MscS), potassium-dependent (MscK) and mini (MscM) conductances. These channels act as 'emergency relief valves' protecting bacteria from lysis upon acute osmotic down-shock. Among them, MscL has been intensively studied since the original identification and characterization 15 years ago. MscL is reversibly and directly gated by changes in membrane tension. In the open state, MscL forms a non-selective 3 nS conductance channel which gates at tensions close to the lytic limit of the bacterial membrane. An earlier crystal structure at 3.5 A resolution of a pentameric MscL from Mycobacterium tuberculosis represents a closed-state or non-conducting conformation. MscL has a complex gating behaviour; it exhibits several intermediates between the closed and open states, including one putative non-conductive expanded state and at least three sub-conducting states. Although our understanding of the closed and open states of MscL has been increasing, little is known about the structures of the intermediate states despite their importance in elucidating the complete gating process of MscL. Here we present the crystal structure of a carboxy-terminal truncation mutant (Delta95-120) of MscL from Staphylococcus aureus (SaMscL(CDelta26)) at 3.8 A resolution. Notably, SaMscL(CDelta26) forms a tetrameric channel with both transmembrane helices tilted away from the membrane normal at angles close to that inferred for the open state, probably corresponding to a non-conductive but partially expanded intermediate state.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2737600/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2737600/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Zhenfeng -- Gandhi, Chris S -- Rees, Douglas C -- GM084211/GM/NIGMS NIH HHS/ -- R01 GM084211/GM/NIGMS NIH HHS/ -- R01 GM084211-01/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Sep 3;461(7260):120-4. doi: 10.1038/nature08277. Epub 2009 Aug 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19701184" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Bacterial Proteins/*chemistry/metabolism ; Crystallography, X-Ray ; Ion Channel Gating ; Ion Channels/*chemistry/metabolism ; Models, Biological ; Models, Molecular ; Molecular Sequence Data ; Mycobacterium tuberculosis/chemistry/metabolism ; Pressure ; Protein Structure, Quaternary ; Staphylococcus aureus/*chemistry ; Structural Homology, Protein
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    An oestrogen-receptor-alpha-bound human chromatin interactome (2009)
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    Publication Date: 2009-11-06
    Description: Genomes are organized into high-level three-dimensional structures, and DNA elements separated by long genomic distances can in principle interact functionally. Many transcription factors bind to regulatory DNA elements distant from gene promoters. Although distal binding sites have been shown to regulate transcription by long-range chromatin interactions at a few loci, chromatin interactions and their impact on transcription regulation have not been investigated in a genome-wide manner. Here we describe the development of a new strategy, chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) for the de novo detection of global chromatin interactions, with which we have comprehensively mapped the chromatin interaction network bound by oestrogen receptor alpha (ER-alpha) in the human genome. We found that most high-confidence remote ER-alpha-binding sites are anchored at gene promoters through long-range chromatin interactions, suggesting that ER-alpha functions by extensive chromatin looping to bring genes together for coordinated transcriptional regulation. We propose that chromatin interactions constitute a primary mechanism for regulating transcription in mammalian genomes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2774924/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2774924/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fullwood, Melissa J -- Liu, Mei Hui -- Pan, You Fu -- Liu, Jun -- Xu, Han -- Mohamed, Yusoff Bin -- Orlov, Yuriy L -- Velkov, Stoyan -- Ho, Andrea -- Mei, Poh Huay -- Chew, Elaine G Y -- Huang, Phillips Yao Hui -- Welboren, Willem-Jan -- Han, Yuyuan -- Ooi, Hong Sain -- Ariyaratne, Pramila N -- Vega, Vinsensius B -- Luo, Yanquan -- Tan, Peck Yean -- Choy, Pei Ye -- Wansa, K D Senali Abayratna -- Zhao, Bing -- Lim, Kar Sian -- Leow, Shi Chi -- Yow, Jit Sin -- Joseph, Roy -- Li, Haixia -- Desai, Kartiki V -- Thomsen, Jane S -- Lee, Yew Kok -- Karuturi, R Krishna Murthy -- Herve, Thoreau -- Bourque, Guillaume -- Stunnenberg, Hendrik G -- Ruan, Xiaoan -- Cacheux-Rataboul, Valere -- Sung, Wing-Kin -- Liu, Edison T -- Wei, Chia-Lin -- Cheung, Edwin -- Ruan, Yijun -- 1U54HG004557-01/HG/NHGRI NIH HHS/ -- R01 HG004456/HG/NHGRI NIH HHS/ -- R01 HG004456-01/HG/NHGRI NIH HHS/ -- R01 HG004456-02/HG/NHGRI NIH HHS/ -- R01 HG004456-03/HG/NHGRI NIH HHS/ -- R01HG003521-01/HG/NHGRI NIH HHS/ -- R01HG004456-01/HG/NHGRI NIH HHS/ -- U54 HG004557/HG/NHGRI NIH HHS/ -- U54 HG004557-01/HG/NHGRI NIH HHS/ -- U54 HG004557-02/HG/NHGRI NIH HHS/ -- U54 HG004557-03/HG/NHGRI NIH HHS/ -- U54 HG004557-04/HG/NHGRI NIH HHS/ -- England -- Nature. 2009 Nov 5;462(7269):58-64. doi: 10.1038/nature08497.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore 138672.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19890323" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Cell Line ; Chromatin/*genetics/*metabolism ; Chromatin Immunoprecipitation ; Cross-Linking Reagents ; Estrogen Receptor alpha/*metabolism ; Formaldehyde ; Genome, Human/*genetics ; Humans ; Promoter Regions, Genetic/genetics ; Protein Binding ; Reproducibility of Results ; Sequence Analysis, DNA ; Transcription, Genetic ; Transcriptional Activation
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    Membrane-protein structure: Piercing insights (2009)
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    Publication Date: 2009-06-06
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bayley, Hagan -- England -- Nature. 2009 Jun 4;459(7247):651-2. doi: 10.1038/459651a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19494904" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*biosynthesis/chemistry/*metabolism ; Escherichia coli/chemistry/metabolism ; Hemolysin Proteins/*biosynthesis/chemistry/*metabolism ; Membrane Proteins/chemistry/metabolism ; Protein Binding ; Protein Structure, Secondary ; Salmonella enterica/chemistry/metabolism
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    Structural insights into mechanisms of the small RNA methyltransferase HEN1 (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-10-09
    Description: RNA silencing is a conserved regulatory mechanism in fungi, plants and animals that regulates gene expression and defence against viruses and transgenes. Small silencing RNAs of approximately 20-30 nucleotides and their associated effector proteins, the Argonaute family proteins, are the central components in RNA silencing. A subset of small RNAs, such as microRNAs and small interfering RNAs (siRNAs) in plants, Piwi-interacting RNAs in animals and siRNAs in Drosophila, requires an additional crucial step for their maturation; that is, 2'-O-methylation on the 3' terminal nucleotide. A conserved S-adenosyl-l-methionine-dependent RNA methyltransferase, HUA ENHANCER 1 (HEN1), and its homologues are responsible for this specific modification. Here we report the 3.1 A crystal structure of full-length HEN1 from Arabidopsis in complex with a 22-nucleotide small RNA duplex and cofactor product S-adenosyl-l-homocysteine. Highly cooperative recognition of the small RNA substrate by multiple RNA binding domains and the methyltransferase domain in HEN1 measures the length of the RNA duplex and determines the substrate specificity. Metal ion coordination by both 2' and 3' hydroxyls on the 3'-terminal nucleotide and four invariant residues in the active site of the methyltransferase domain suggests a novel Mg(2+)-dependent 2'-O-methylation mechanism.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Ying -- Ji, Lijuan -- Huang, Qichen -- Vassylyev, Dmitry G -- Chen, Xuemei -- Ma, Jin-Biao -- GM074252/GM/NIGMS NIH HHS/ -- R01 GM074840/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Oct 8;461(7265):823-7. doi: 10.1038/nature08433.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Genetics, Schools of Medicine and Dentistry, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19812675" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Arabidopsis/*enzymology/genetics ; Arabidopsis Proteins/*chemistry/genetics/*metabolism ; Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; Magnesium/metabolism ; Methylation ; Methyltransferases/*chemistry/*metabolism ; Models, Biological ; Models, Molecular ; Protein Structure, Tertiary ; RNA/genetics/*metabolism ; RNA-Binding Proteins/chemistry/metabolism ; S-Adenosylhomocysteine/chemistry/metabolism ; Structure-Activity Relationship ; Substrate Specificity
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Biochemistry: Enzyme's black box cracked open (2009)
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    Publication Date: 2009-10-23
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sherman, David H -- England -- Nature. 2009 Oct 22;461(7267):1068-9. doi: 10.1038/4611068a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19847256" target="_blank"〉PubMed〈/a〉
    Keywords: Aflatoxin B1/biosynthesis ; Aspergillus/*enzymology ; Catalytic Domain ; Crystallography, X-Ray ; Cyclization ; Pantetheine/analogs & derivatives/metabolism ; Polyketide Synthases/*chemistry/*metabolism ; Protein Structure, Tertiary ; Structure-Activity Relationship
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    Structures of the tRNA export factor in the nuclear and cytosolic states (2009)
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    Publication Date: 2009-08-15
    Description: Transfer RNAs are among the most ubiquitous molecules in cells, central to decoding information from messenger RNAs on translating ribosomes. In eukaryotic cells, tRNAs are actively transported from their site of synthesis in the nucleus to their site of function in the cytosol. This is mediated by a dedicated nucleo-cytoplasmic transport factor of the karyopherin-beta family (Xpot, also known as Los1 in Saccharomyces cerevisiae). Here we report the 3.2 A resolution structure of Schizosaccharomyces pombe Xpot in complex with tRNA and RanGTP, and the 3.1 A structure of unbound Xpot, revealing both nuclear and cytosolic snapshots of this transport factor. Xpot undergoes a large conformational change on binding cargo, wrapping around the tRNA and, in particular, binding to the tRNA 5' and 3' ends. The binding mode explains how Xpot can recognize all mature tRNAs in the cell and yet distinguish them from those that have not been properly processed, thus coupling tRNA export to quality control.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cook, Atlanta G -- Fukuhara, Noemi -- Jinek, Martin -- Conti, Elena -- England -- Nature. 2009 Sep 3;461(7260):60-5. doi: 10.1038/nature08394.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Cell Biology, MPI for Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19680239" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Cell Nucleus/*metabolism ; Crystallography, X-Ray ; Cytosol/*metabolism ; GTPase-Activating Proteins/chemistry/metabolism ; Models, Molecular ; Nuclear Pore Complex Proteins/*chemistry/*metabolism ; Protein Binding ; Protein Conformation ; *RNA Transport ; RNA, Fungal/chemistry/genetics/metabolism ; RNA, Transfer/chemistry/genetics/*metabolism ; RNA, Transfer, Phe/chemistry/genetics/metabolism ; Saccharomyces cerevisiae Proteins/chemistry/metabolism ; Schizosaccharomyces pombe Proteins/*chemistry/*metabolism ; Substrate Specificity ; ran GTP-Binding Protein/chemistry/metabolism
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    Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling (2009)
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    Publication Date: 2009-09-18
    Description: The stability of the Wnt pathway transcription factor beta-catenin is tightly regulated by the multi-subunit destruction complex. Deregulated Wnt pathway activity has been implicated in many cancers, making this pathway an attractive target for anticancer therapies. However, the development of targeted Wnt pathway inhibitors has been hampered by the limited number of pathway components that are amenable to small molecule inhibition. Here, we used a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits beta-catenin-mediated transcription. XAV939 stimulates beta-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. Thus, our study provides new mechanistic insights into the regulation of axin protein homeostasis and presents new avenues for targeted Wnt pathway therapies.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Shih-Min A -- Mishina, Yuji M -- Liu, Shanming -- Cheung, Atwood -- Stegmeier, Frank -- Michaud, Gregory A -- Charlat, Olga -- Wiellette, Elizabeth -- Zhang, Yue -- Wiessner, Stephanie -- Hild, Marc -- Shi, Xiaoying -- Wilson, Christopher J -- Mickanin, Craig -- Myer, Vic -- Fazal, Aleem -- Tomlinson, Ronald -- Serluca, Fabrizio -- Shao, Wenlin -- Cheng, Hong -- Shultz, Michael -- Rau, Christina -- Schirle, Markus -- Schlegl, Judith -- Ghidelli, Sonja -- Fawell, Stephen -- Lu, Chris -- Curtis, Daniel -- Kirschner, Marc W -- Lengauer, Christoph -- Finan, Peter M -- Tallarico, John A -- Bouwmeester, Tewis -- Porter, Jeffery A -- Bauer, Andreas -- Cong, Feng -- England -- Nature. 2009 Oct 1;461(7264):614-20. doi: 10.1038/nature08356. Epub 2009 Sep 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19759537" target="_blank"〉PubMed〈/a〉
    Keywords: Axin Protein ; Cell Division/drug effects ; Cell Line ; Cell Line, Tumor ; Colorectal Neoplasms/drug therapy/metabolism ; Heterocyclic Compounds, 3-Ring/pharmacology ; Humans ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding ; Proteomics ; Repressor Proteins/chemistry/*metabolism ; Signal Transduction/*drug effects ; Tankyrases/*antagonists & inhibitors/metabolism ; Transcription, Genetic/drug effects ; Ubiquitin/metabolism ; Ubiquitination ; Wnt Proteins/*antagonists & inhibitors/metabolism ; beta Catenin/antagonists & inhibitors/metabolism
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    Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger (2009)
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    Publication Date: 2009-05-12
    Description: Histone H3 lysine 4 methylation (H3K4me) has been proposed as a critical component in regulating gene expression, epigenetic states, and cellular identities1. The biological meaning of H3K4me is interpreted by conserved modules including plant homeodomain (PHD) fingers that recognize varied H3K4me states. The dysregulation of PHD fingers has been implicated in several human diseases, including cancers and immune or neurological disorders. Here we report that fusing an H3K4-trimethylation (H3K4me3)-binding PHD finger, such as the carboxy-terminal PHD finger of PHF23 or JARID1A (also known as KDM5A or RBBP2), to a common fusion partner nucleoporin-98 (NUP98) as identified in human leukaemias, generated potent oncoproteins that arrested haematopoietic differentiation and induced acute myeloid leukaemia in murine models. In these processes, a PHD finger that specifically recognizes H3K4me3/2 marks was essential for leukaemogenesis. Mutations in PHD fingers that abrogated H3K4me3 binding also abolished leukaemic transformation. NUP98-PHD fusion prevented the differentiation-associated removal of H3K4me3 at many loci encoding lineage-specific transcription factors (Hox(s), Gata3, Meis1, Eya1 and Pbx1), and enforced their active gene transcription in murine haematopoietic stem/progenitor cells. Mechanistically, NUP98-PHD fusions act as 'chromatin boundary factors', dominating over polycomb-mediated gene silencing to 'lock' developmentally critical loci into an active chromatin state (H3K4me3 with induced histone acetylation), a state that defined leukaemia stem cells. Collectively, our studies represent, to our knowledge, the first report that deregulation of the PHD finger, an 'effector' of specific histone modification, perturbs the epigenetic dynamics on developmentally critical loci, catastrophizes cellular fate decision-making, and even causes oncogenesis during mammalian development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2697266/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2697266/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Gang G -- Song, Jikui -- Wang, Zhanxin -- Dormann, Holger L -- Casadio, Fabio -- Li, Haitao -- Luo, Jun-Li -- Patel, Dinshaw J -- Allis, C David -- K99 CA151683/CA/NCI NIH HHS/ -- R37 GM053512/GM/NIGMS NIH HHS/ -- R37 GM053512-30/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Jun 11;459(7248):847-51. doi: 10.1038/nature08036.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Chromatin Biology & Epigenetics, The Rockefeller University, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19430464" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs/genetics/physiology ; Animals ; Cell Transformation, Neoplastic ; Cells, Cultured ; Chromatin/*metabolism ; Epigenesis, Genetic ; Gene Expression Regulation, Developmental ; Genes, Homeobox/genetics ; Hematologic Neoplasms/genetics/*metabolism/*pathology ; Hematopoiesis/genetics ; Hematopoietic Stem Cells/metabolism/pathology ; Histones/chemistry/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/*chemistry/genetics/*metabolism ; Lysine/metabolism ; Magnetic Resonance Spectroscopy ; Methylation ; Mice ; Models, Molecular ; Nuclear Pore Complex Proteins/chemistry/genetics/metabolism ; Oncogene Proteins, Fusion/*chemistry/genetics/*metabolism ; Protein Binding ; Protein Conformation ; Retinoblastoma-Binding Protein 2 ; Transcription, Genetic ; Tumor Suppressor Proteins/*chemistry/genetics/*metabolism
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    Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions (2009)
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    Publication Date: 2009-02-24
    Description: Life and death fate decisions allow cells to avoid massive apoptotic death in response to genotoxic stress. Although the regulatory mechanisms and signalling pathways controlling DNA repair and apoptosis are well characterized, the precise molecular strategies that determine the ultimate choice of DNA repair and survival or apoptotic cell death remain incompletely understood. Here we report that a protein tyrosine phosphatase, EYA, is involved in promoting efficient DNA repair rather than apoptosis in response to genotoxic stress in mammalian embryonic kidney cells by executing a damage-signal-dependent dephosphorylation of an H2AX carboxy-terminal tyrosine phosphate (Y142). This post-translational modification determines the relative recruitment of either DNA repair or pro-apoptotic factors to the tail of serine phosphorylated histone H2AX (gamma-H2AX) and allows it to function as an active determinant of repair/survival versus apoptotic responses to DNA damage, revealing an additional phosphorylation-dependent mechanism that modulates survival/apoptotic decisions during mammalian organogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2692521/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2692521/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cook, Peter J -- Ju, Bong Gun -- Telese, Francesca -- Wang, Xiangting -- Glass, Christopher K -- Rosenfeld, Michael G -- R01 CA097134/CA/NCI NIH HHS/ -- R01 CA097134-06A1/CA/NCI NIH HHS/ -- R01 CA097134-07/CA/NCI NIH HHS/ -- R01 DK039949/DK/NIDDK NIH HHS/ -- R01 DK039949-17S1/DK/NIDDK NIH HHS/ -- R01 DK039949-18/DK/NIDDK NIH HHS/ -- R01 HL065445/HL/NHLBI NIH HHS/ -- R01 HL065445-08/HL/NHLBI NIH HHS/ -- R01 HL065445-09/HL/NHLBI NIH HHS/ -- R01 NS034934/NS/NINDS NIH HHS/ -- R01 NS034934-18/NS/NINDS NIH HHS/ -- R01 NS034934-19/NS/NINDS NIH HHS/ -- R01 NS034934-20A1/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Apr 2;458(7238):591-6. doi: 10.1038/nature07849. Epub 2009 Feb 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute School of Medicine, University of California, San Diego, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19234442" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Apoptosis ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/metabolism ; Cell Line ; Cell Survival ; DNA Damage ; DNA Repair ; DNA-Binding Proteins/deficiency/genetics/metabolism ; Histones/deficiency/genetics/*metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/deficiency/genetics/metabolism ; Mice ; Nuclear Proteins/deficiency/genetics/metabolism ; Phosphorylation ; Phosphotyrosine/metabolism ; Protein Binding ; Protein Tyrosine Phosphatases/deficiency/genetics/metabolism ; Protein-Serine-Threonine Kinases/metabolism ; Substrate Specificity ; Tumor Suppressor Proteins/metabolism ; Tyrosine/*metabolism
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    A mutation in Ihh that causes digit abnormalities alters its signalling capacity and range (2009)
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    Publication Date: 2009-03-03
    Description: Brachydactyly type A1 (BDA1) was the first recorded disorder of the autosomal dominant Mendelian trait in humans, characterized by shortened or absent middle phalanges in digits. It is associated with heterozygous missense mutations in indian hedgehog (IHH). Hedgehog proteins are important morphogens for a wide range of developmental processes. The capacity and range of signalling is thought to be regulated by its interaction with the receptor PTCH1 and antagonist HIP1. Here we show that a BDA1 mutation (E95K) in Ihh impairs the interaction of IHH with PTCH1 and HIP1. This is consistent with a recent paper showing that BDA1 mutations cluster in a calcium-binding site essential for the interaction with its receptor and cell-surface partners. Furthermore, we show that in a mouse model that recapitulates the E95K mutation, there is a change in the potency and range of signalling. The mice have digit abnormalities consistent with the human disorder.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gao, Bo -- Hu, Jianxin -- Stricker, Sigmar -- Cheung, Martin -- Ma, Gang -- Law, Kit Fong -- Witte, Florian -- Briscoe, James -- Mundlos, Stefan -- He, Lin -- Cheah, Kathryn S E -- Chan, Danny -- MC_U117560541/Medical Research Council/United Kingdom -- England -- Nature. 2009 Apr 30;458(7242):1196-200. doi: 10.1038/nature07862. Epub 2009 Mar 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, the University of Hong Kong, Hong Kong, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19252479" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chickens ; DNA-Binding Proteins/genetics/metabolism ; Disease Models, Animal ; Female ; Hedgehog Proteins/*genetics/*metabolism ; Humans ; Limb Deformities, Congenital/*genetics/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Mutation/*genetics ; Protein Binding ; Receptors, Cell Surface/genetics/metabolism ; *Signal Transduction
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    Crystal structure of the sodium-potassium pump at 2.4 A resolution (2009)
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    Publication Date: 2009-05-22
    Description: Sodium-potassium ATPase is an ATP-powered ion pump that establishes concentration gradients for Na(+) and K(+) ions across the plasma membrane in all animal cells by pumping Na(+) from the cytoplasm and K(+) from the extracellular medium. Such gradients are used in many essential processes, notably for generating action potentials. Na(+), K(+)-ATPase is a member of the P-type ATPases, which include sarcoplasmic reticulum Ca(2+)-ATPase and gastric H(+), K(+)-ATPase, among others, and is the target of cardiac glycosides. Here we describe a crystal structure of this important ion pump, from shark rectal glands, consisting of alpha- and beta-subunits and a regulatory FXYD protein, all of which are highly homologous to human ones. The ATPase was fixed in a state analogous to E2.2K(+).P(i), in which the ATPase has a high affinity for K(+) and still binds P(i), as in the first crystal structure of pig kidney enzyme at 3.5 A resolution. Clearly visualized now at 2.4 A resolution are coordination of K(+) and associated water molecules in the transmembrane binding sites and a phosphate analogue (MgF(4)(2-)) in the phosphorylation site. The crystal structure shows that the beta-subunit has a critical role in K(+) binding (although its involvement has previously been suggested) and explains, at least partially, why the homologous Ca(2+)-ATPase counter-transports H(+) rather than K(+), despite the coordinating residues being almost identical.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shinoda, Takehiro -- Ogawa, Haruo -- Cornelius, Flemming -- Toyoshima, Chikashi -- England -- Nature. 2009 May 21;459(7245):446-50. doi: 10.1038/nature07939.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19458722" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Calcium-Transporting ATPases/chemistry/metabolism ; Crystallography, X-Ray ; Fluorides/metabolism ; Humans ; Magnesium Compounds/metabolism ; Membrane Proteins/chemistry/metabolism ; Models, Molecular ; Phosphoproteins/chemistry/metabolism ; Phosphorylation ; Potassium/metabolism ; Protein Conformation ; Protein Subunits/chemistry/metabolism ; Salt Gland/enzymology ; Sharks ; Sodium-Potassium-Exchanging ATPase/*chemistry/metabolism ; Swine
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    Biochemistry: Anchors away (2009)
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    Publication Date: 2009-04-17
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Costi, Maria Paola -- Ferrari, Stefania -- England -- Nature. 2009 Apr 16;458(7240):840-1. doi: 10.1038/458840a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19370021" target="_blank"〉PubMed〈/a〉
    Keywords: Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; Deoxyuracil Nucleotides/chemistry/metabolism ; Flavin-Adenine Dinucleotide/analogs & derivatives/chemistry/metabolism ; Flavins/chemistry/*metabolism ; Helicobacter pylori/enzymology/genetics ; Humans ; Thermotoga maritima/*enzymology/genetics/*metabolism ; Thymidine Monophosphate/*biosynthesis ; Thymidylate Synthase/antagonists & inhibitors/*genetics/*metabolism ; Uracil/metabolism
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    Protein structures: Structures of desire (2009)
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    Publication Date: 2009-05-09
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bhattacharya, Ananyo -- England -- Nature. 2009 May 7;459(7243):24-7. doi: 10.1038/459024a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19424134" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bacteria/chemistry ; Crystallography, X-Ray ; Eukaryotic Cells/chemistry ; Humans ; *Models, Molecular ; Nuclear Pore/chemistry ; Proteins/*chemistry ; Receptor, Epidermal Growth Factor/chemistry ; Ribosomes/chemistry ; Spliceosomes/chemistry
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    Structure of the formate transporter FocA reveals a pentameric aquaporin-like channel (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-11-27
    Description: FocA is a representative member of the formate-nitrite transporter family, which transports short-chain acids in bacteria, archaea, fungi, algae and parasites. The structure and transport mechanism of the formate-nitrite transporter family remain unknown. Here we report the crystal structure of Escherichia coli FocA at 2.25 A resolution. FocA forms a symmetric pentamer, with each protomer consisting of six transmembrane segments. Despite a lack of sequence homology, the overall structure of the FocA protomer closely resembles that of aquaporin and strongly argues that FocA is a channel, rather than a transporter. Structural analysis identifies potentially important channel residues, defines the channel path and reveals two constriction sites. Unlike aquaporin, FocA is impermeable to water but allows the passage of formate. A structural and biochemical investigation provides mechanistic insights into the channel activity of FocA.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Yi -- Huang, Yongjian -- Wang, Jiawei -- Cheng, Chao -- Huang, Weijiao -- Lu, Peilong -- Xu, Ya-Nan -- Wang, Pengye -- Yan, Nieng -- Shi, Yigong -- England -- Nature. 2009 Nov 26;462(7272):467-72. doi: 10.1038/nature08610.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ministry of Education Protein Science Laboratory, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19940917" target="_blank"〉PubMed〈/a〉
    Keywords: Aquaporins/*chemistry/metabolism ; Crystallography, X-Ray ; Escherichia coli/chemistry/genetics/metabolism ; Escherichia coli Proteins/*chemistry/genetics/metabolism ; Formates/metabolism ; Liposomes/chemistry/metabolism ; Membrane Transport Proteins/*chemistry/genetics/metabolism ; Models, Molecular ; Molecular Mimicry ; Mutation ; Permeability ; Protein Structure, Quaternary ; Structure-Activity Relationship ; Water/analysis/metabolism
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    Nucleation, propagation and cleavage of target RNAs in Ago silencing complexes (2009)
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    Publication Date: 2009-10-09
    Description: The slicer activity of the RNA-induced silencing complex resides within its Argonaute (Ago) component, in which the PIWI domain provides the catalytic residues governing guide-strand mediated site-specific cleavage of target RNA. Here we report on structures of ternary complexes of Thermus thermophilus Ago catalytic mutants with 5'-phosphorylated 21-nucleotide guide DNA and complementary target RNAs of 12, 15 and 19 nucleotides in length, which define the molecular basis for Mg(2+)-facilitated site-specific cleavage of the target. We observe pivot-like domain movements within the Ago scaffold on proceeding from nucleation to propagation steps of guide-target duplex formation, with duplex zippering beyond one turn of the helix requiring the release of the 3'-end of the guide from the PAZ pocket. Cleavage assays on targets of various lengths supported this model, and sugar-phosphate-backbone-modified target strands showed the importance of structural and catalytic divalent metal ions observed in the crystal structures.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880917/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880917/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Yanli -- Juranek, Stefan -- Li, Haitao -- Sheng, Gang -- Wardle, Greg S -- Tuschl, Thomas -- Patel, Dinshaw J -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 AI068776/AI/NIAID NIH HHS/ -- R01 AI068776-04/AI/NIAID NIH HHS/ -- R01 AI068776-05/AI/NIAID NIH HHS/ -- R01 GM068476/GM/NIGMS NIH HHS/ -- R01 GM068476-05/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Oct 8;461(7265):754-61. doi: 10.1038/nature08434.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Biology Program, Memorial-Sloan Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19812667" target="_blank"〉PubMed〈/a〉
    Keywords: Base Pairing ; Biocatalysis ; Catalytic Domain/genetics ; Cations, Divalent/metabolism ; Crystallography, X-Ray ; DNA/chemistry/genetics/metabolism ; *Gene Silencing ; Magnesium/metabolism ; Models, Molecular ; Phosphorylation ; RNA/chemistry/genetics/*metabolism ; RNA-Induced Silencing Complex/*chemistry/genetics/*metabolism ; Structure-Activity Relationship ; Substrate Specificity ; Thermus thermophilus/*enzymology/genetics
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    Structural biology: Trimeric ion-channel design (2009)
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    Publication Date: 2009-07-31
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Silberberg, Shai D -- Swartz, Kenton J -- ZIA NS003018-03/Intramural NIH HHS/ -- England -- Nature. 2009 Jul 30;460(7255):580-1. doi: 10.1038/460580a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19641581" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Ion Channels/*chemistry ; Membrane Proteins/*chemistry ; *Models, Molecular ; Protein Binding ; Protein Structure, Tertiary ; Receptors, Purinergic P2/*chemistry
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    High-resolution multi-dimensional NMR spectroscopy of proteins in human cells (2009)
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    Publication Date: 2009-03-06
    Description: In-cell NMR is an isotope-aided multi-dimensional NMR technique that enables observations of conformations and functions of proteins in living cells at the atomic level. This method has been successfully applied to proteins overexpressed in bacteria, providing information on protein-ligand interactions and conformations. However, the application of in-cell NMR to eukaryotic cells has been limited to Xenopus laevis oocytes. Wider application of the technique is hampered by inefficient delivery of isotope-labelled proteins into eukaryote somatic cells. Here we describe a method to obtain high-resolution two-dimensional (2D) heteronuclear NMR spectra of proteins inside living human cells. Proteins were delivered to the cytosol by the pyrenebutyrate-mediated action of cell-penetrating peptides linked covalently to the proteins. The proteins were subsequently released from cell-penetrating peptides by endogenous enzymatic activity or by autonomous reductive cleavage. The heteronuclear 2D spectra of three different proteins inside human cells demonstrate the broad application of this technique to studying interactions and protein processing. The in-cell NMR spectra of FKBP12 (also known as FKBP1A) show the formation of specific complexes between the protein and extracellularly administered immunosuppressants, demonstrating the utility of this technique in drug screening programs. Moreover, in-cell NMR spectroscopy demonstrates that ubiquitin has much higher hydrogen exchange rates in the intracellular environment, possibly due to multiple interactions with endogenous proteins.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Inomata, Kohsuke -- Ohno, Ayako -- Tochio, Hidehito -- Isogai, Shin -- Tenno, Takeshi -- Nakase, Ikuhiko -- Takeuchi, Toshihide -- Futaki, Shiroh -- Ito, Yutaka -- Hiroaki, Hidekazu -- Shirakawa, Masahiro -- England -- Nature. 2009 Mar 5;458(7234):106-9. doi: 10.1038/nature07839.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Engineering, Graduate School of Engineering, Kyoto University, Nishikyo-Ku, Kyoto 615-8510, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19262675" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Membrane Permeability ; Cell Survival/drug effects ; Deuterium Exchange Measurement ; Drug Evaluation, Preclinical/methods ; Gene Products, tat/genetics/metabolism ; HeLa Cells ; Humans ; Immunosuppressive Agents/chemistry/metabolism/pharmacology ; Intracellular Space/*metabolism ; Nuclear Magnetic Resonance, Biomolecular/*methods ; Protein Binding ; Pyrenes/pharmacology ; Recombinant Fusion Proteins/*chemistry/genetics/metabolism ; Tacrolimus Binding Protein 1A/chemistry/genetics/metabolism ; Transfection ; Ubiquitin/genetics/metabolism
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    Casein kinase 1alpha governs antigen-receptor-induced NF-kappaB activation and human lymphoma cell survival (2009)
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    Publication Date: 2009-01-02
    Description: The transcription factor NF-kappaB is required for lymphocyte activation and proliferation as well as the survival of certain lymphoma types. Antigen receptor stimulation assembles an NF-kappaB activating platform containing the scaffold protein CARMA1 (also called CARD11), the adaptor BCL10 and the paracaspase MALT1 (the CBM complex), linked to the inhibitor of NF-kappaB kinase complex, but signal transduction is not fully understood. We conducted parallel screens involving a mass spectrometry analysis of CARMA1 binding partners and an RNA interference screen for growth inhibition of the CBM-dependent 'activated B-cell-like' (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). Here we report that both screens identified casein kinase 1alpha (CK1alpha) as a bifunctional regulator of NF-kappaB. CK1alpha dynamically associates with the CBM complex on T-cell-receptor (TCR) engagement to participate in cytokine production and lymphocyte proliferation. However, CK1alpha kinase activity has a contrasting role by subsequently promoting the phosphorylation and inactivation of CARMA1. CK1alpha has thus a dual 'gating' function which first promotes and then terminates receptor-induced NF-kappaB. ABC DLBCL cells required CK1alpha for constitutive NF-kappaB activity, indicating that CK1alpha functions as a conditionally essential malignancy gene-a member of a new class of potential cancer therapeutic targets.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688735/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688735/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bidere, Nicolas -- Ngo, Vu N -- Lee, Jeansun -- Collins, Cailin -- Zheng, Lixin -- Wan, Fengyi -- Davis, R Eric -- Lenz, Georg -- Anderson, D Eric -- Arnoult, Damien -- Vazquez, Aime -- Sakai, Keiko -- Zhang, Jun -- Meng, Zhaojing -- Veenstra, Timothy D -- Staudt, Louis M -- Lenardo, Michael J -- NIH0011349228/PHS HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2009 Mar 5;458(7234):92-6. doi: 10.1038/nature07613. Epub 2008 Dec 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Development Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19118383" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/metabolism ; CARD Signaling Adaptor Proteins/metabolism ; Casein Kinases/*metabolism ; Caspases/metabolism ; Cell Proliferation ; Cell Survival ; Cells, Cultured ; Feedback, Physiological ; Guanylate Cyclase/metabolism ; Humans ; I-kappa B Kinase/metabolism ; Jurkat Cells ; Lymphoma, Large B-Cell, Diffuse/enzymology/*metabolism/*pathology ; NF-kappa B/*metabolism ; Neoplasm Proteins/metabolism ; Protein Binding ; Receptors, Antigen/*metabolism ; Signal Transduction
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    Structural basis for biosynthetic programming of fungal aromatic polyketide cyclization (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-10-23
    Description: Polyketides are a class of natural products with diverse structures and biological activities. The structural variability of aromatic products of fungal nonreducing, multidomain iterative polyketide synthases (NR-PKS group of IPKSs) results from regiospecific cyclizations of reactive poly-beta-keto intermediates. How poly-beta-keto species are synthesized and stabilized, how their chain lengths are determined, and, in particular, how specific cyclization patterns are controlled have been largely inaccessible and functionally unknown until recently. A product template (PT) domain is responsible for controlling specific aldol cyclization and aromatization of these mature polyketide precursors, but the mechanistic basis is unknown. Here we present the 1.8 A crystal structure and mutational studies of a dissected PT monodomain from PksA, the NR-PKS that initiates the biosynthesis of the potent hepatocarcinogen aflatoxin B(1) in Aspergillus parasiticus. Despite having minimal sequence similarity to known enzymes, the structure displays a distinct 'double hot dog' (DHD) fold. Co-crystal structures with palmitate or a bicyclic substrate mimic illustrate that PT can bind both linear and bicyclic polyketides. Docking and mutagenesis studies reveal residues important for substrate binding and catalysis, and identify a phosphopantetheine localization channel and a deep two-part interior binding pocket and reaction chamber. Sequence similarity and extensive conservation of active site residues in PT domains suggest that the mechanistic insights gleaned from these studies will prove general for this class of IPKSs, and lay a foundation for defining the molecular rules controlling NR-PKS cyclization specificity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872118/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872118/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Crawford, Jason M -- Korman, Tyler P -- Labonte, Jason W -- Vagstad, Anna L -- Hill, Eric A -- Kamari-Bidkorpeh, Oliver -- Tsai, Shiou-Chuan -- Townsend, Craig A -- ES001670/ES/NIEHS NIH HHS/ -- R01 GM076330/GM/NIGMS NIH HHS/ -- R01 GM076330-01A2/GM/NIGMS NIH HHS/ -- R01 GM076330-02/GM/NIGMS NIH HHS/ -- R01 GM076330-03/GM/NIGMS NIH HHS/ -- R01 GM100305/GM/NIGMS NIH HHS/ -- R37 AI014937/AI/NIAID NIH HHS/ -- R37 AI014937-31/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Oct 22;461(7267):1139-43. doi: 10.1038/nature08475.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Johns Hopkins University, Maryland 21218, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19847268" target="_blank"〉PubMed〈/a〉
    Keywords: Aflatoxin B1/biosynthesis ; Anthracenes/metabolism ; Anthraquinones/metabolism ; Aspergillus/*enzymology ; Catalytic Domain ; Crystallography, X-Ray ; Cyclization ; Models, Molecular ; Oxidation-Reduction ; Palmitic Acid/metabolism ; Polyketide Synthases/*chemistry/*metabolism ; Protein Structure, Tertiary ; Structure-Activity Relationship
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    A secreted complement-control-related protein ensures acetylcholine receptor clustering (2009)
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    Publication Date: 2009-10-02
    Description: Efficient neurotransmission at chemical synapses relies on spatial congruence between the presynaptic active zone, where synaptic vesicles fuse, and the postsynaptic differentiation, where neurotransmitter receptors concentrate. Diverse molecular systems have evolved to localize receptors at synapses, but in most cases, they rely on scaffolding proteins localized below the plasma membrane. A few systems have been suggested to control the synaptic localization of neurotransmitter receptors through extracellular interactions, such as the pentraxins that bind AMPA receptors and trigger their aggregation. However, it is not yet clear whether these systems have a central role in the organization of postsynaptic domains in vivo or rather provide modulatory functions. Here we describe an extracellular scaffold that is necessary to cluster acetylcholine receptors at neuromuscular junctions in the nematode Caenorhabditis elegans. It involves the ectodomain of the previously identified transmembrane protein LEV-10 (ref. 6) and a novel extracellular protein, LEV-9. LEV-9 is secreted by the muscle cells and localizes at cholinergic neuromuscular junctions. Acetylcholine receptors, LEV-9 and LEV-10 are interdependent for proper synaptic localization and physically interact based on biochemical evidence. Notably, the function of LEV-9 relies on eight complement control protein (CCP) domains. These domains, also called 'sushi domains', are usually found in proteins regulating complement activity in the vertebrate immune system. Because the complement system does not exist in protostomes, our results suggest that some of the numerous uncharacterized CCP proteins expressed in the mammalian brain might be directly involved in the organization of the synapse, independently from immune functions.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gendrel, Marie -- Rapti, Georgia -- Richmond, Janet E -- Bessereau, Jean-Louis -- R01 MH073156/MH/NIMH NIH HHS/ -- England -- Nature. 2009 Oct 15;461(7266):992-6. doi: 10.1038/nature08430. Epub 2009 Sep 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉ENS, Biology Department, Paris, F-75005 France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19794415" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Caenorhabditis elegans/cytology/*metabolism ; Caenorhabditis elegans Proteins/*chemistry/genetics/*metabolism/secretion ; Membrane Proteins/genetics/metabolism ; Molecular Sequence Data ; Muscles/metabolism ; Neuromuscular Junction/metabolism ; Organ Specificity ; Protein Binding ; Protein Structure, Tertiary ; Protein Transport ; Receptors, Cholinergic/*metabolism ; Viral Proteins/*chemistry
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    Structural biology: Anticancer drug target pictured (2009)
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    Publication Date: 2009-01-09
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Waterman, Michael R -- England -- Nature. 2009 Jan 8;457(7226):159-60. doi: 10.1038/457159a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19129840" target="_blank"〉PubMed〈/a〉
    Keywords: Aromatase/*chemistry/*metabolism ; Aromatase Inhibitors/*pharmacology/therapeutic use ; Breast Neoplasms/*drug therapy/*enzymology/metabolism ; Catalytic Domain ; Crystallography, X-Ray ; Estrogens/*biosynthesis ; Female ; Humans
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    An unexpected twist in viral capsid maturation (2009)
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    Publication Date: 2009-02-11
    Description: Lambda-like double-stranded (ds) DNA bacteriophage undergo massive conformational changes in their capsid shell during the packaging of their viral genomes. Capsid shells are complex organizations of hundreds of protein subunits that assemble into intricate quaternary complexes that ultimately are able to withstand over 50 atm of pressure during genome packaging. The extensive integration between subunits in capsids requires the formation of an intermediate complex, termed a procapsid, from which individual subunits can undergo the necessary refolding and structural rearrangements needed to transition to the more stable capsid. Although various mature capsids have been characterized at atomic resolution, no such procapsid structure is available for a dsDNA virus or bacteriophage. Here we present a procapsid X-ray structure at 3.65 A resolution, termed prohead II, of the lambda-like bacteriophage HK97, the mature capsid structure of which was previously solved to 3.44 A (ref. 2). A comparison of the two largely different capsid forms has unveiled an unprecedented expansion mechanism that describes the transition. Crystallographic and hydrogen/deuterium exchange data presented here demonstrate that the subunit tertiary structures are significantly different between the two states, with twisting and bending motions occurring in both helical and beta-sheet regions. We also identified subunit interactions at each three-fold axis of the capsid that are maintained throughout maturation. The interactions sustain capsid integrity during subunit refolding and provide a fixed hinge from which subunits undergo rotational and translational motions during maturation. Previously published calorimetric data of a closely related bacteriophage, P22, showed that capsid maturation was an exothermic process that resulted in a release of 90 kJ mol(-1) of energy. We propose that the major tertiary changes presented in this study reveal a structural basis for an exothermic maturation process probably present in many dsDNA bacteriophage and possibly viruses such as herpesvirus, which share the HK97 subunit fold.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2765791/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2765791/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gertsman, Ilya -- Gan, Lu -- Guttman, Miklos -- Lee, Kelly -- Speir, Jeffrey A -- Duda, Robert L -- Hendrix, Roger W -- Komives, Elizabeth A -- Johnson, John E -- GM08326/GM/NIGMS NIH HHS/ -- R01 AI040101/AI/NIAID NIH HHS/ -- R01 AI040101-04/AI/NIAID NIH HHS/ -- R01 AI040101-14/AI/NIAID NIH HHS/ -- R01 AI40101/AI/NIAID NIH HHS/ -- R01 GM47795/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Apr 2;458(7238):646-50. doi: 10.1038/nature07686. Epub 2009 Feb 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19204733" target="_blank"〉PubMed〈/a〉
    Keywords: Capsid/*chemistry/*metabolism ; Capsid Proteins/chemistry/genetics/metabolism ; Crystallography, X-Ray ; Deuterium Exchange Measurement ; Models, Molecular ; Movement ; Protein Conformation ; Protein Folding ; Protein Multimerization ; Protein Subunits/chemistry/metabolism ; Siphoviridae/*chemistry/genetics/*growth & development ; Thermodynamics ; *Virus Assembly
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    Structural basis for androgen specificity and oestrogen synthesis in human aromatase (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-01-09
    Description: Aromatase cytochrome P450 is the only enzyme in vertebrates known to catalyse the biosynthesis of all oestrogens from androgens. Aromatase inhibitors therefore constitute a frontline therapy for oestrogen-dependent breast cancer. In a three-step process, each step requiring 1 mol of O(2), 1 mol of NADPH, and coupling with its redox partner cytochrome P450 reductase, aromatase converts androstenedione, testosterone and 16alpha-hydroxytestosterone to oestrone, 17beta-oestradiol and 17beta,16alpha-oestriol, respectively. The first two steps are C19-methyl hydroxylation steps, and the third involves the aromatization of the steroid A-ring, unique to aromatase. Whereas most P450s are not highly substrate selective, it is the hallmark androgenic specificity that sets aromatase apart. The structure of this enzyme of the endoplasmic reticulum membrane has remained unknown for decades, hindering elucidation of the biochemical mechanism. Here we present the crystal structure of human placental aromatase, the only natural mammalian, full-length P450 and P450 in hormone biosynthetic pathways to be crystallized so far. Unlike the active sites of many microsomal P450s that metabolize drugs and xenobiotics, aromatase has an androgen-specific cleft that binds the androstenedione molecule snugly. Hydrophobic and polar residues exquisitely complement the steroid backbone. The locations of catalytically important residues shed light on the reaction mechanism. The relative juxtaposition of the hydrophobic amino-terminal region and the opening to the catalytic cleft shows why membrane anchoring is necessary for the lipophilic substrates to gain access to the active site. The molecular basis for the enzyme's androgenic specificity and unique catalytic mechanism can be used for developing next-generation aromatase inhibitors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2820300/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2820300/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ghosh, Debashis -- Griswold, Jennifer -- Erman, Mary -- Pangborn, Walter -- GM59450/GM/NIGMS NIH HHS/ -- GM62794/GM/NIGMS NIH HHS/ -- R01 GM062794/GM/NIGMS NIH HHS/ -- R01 GM062794-01A1/GM/NIGMS NIH HHS/ -- R01 GM062794-02/GM/NIGMS NIH HHS/ -- R01 GM062794-03/GM/NIGMS NIH HHS/ -- R01 GM062794-04/GM/NIGMS NIH HHS/ -- R01 GM086893/GM/NIGMS NIH HHS/ -- R01 GM086893-01A1/GM/NIGMS NIH HHS/ -- R21 GM059450/GM/NIGMS NIH HHS/ -- R21 GM059450-01/GM/NIGMS NIH HHS/ -- R21 GM059450-02/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Jan 8;457(7226):219-23. doi: 10.1038/nature07614.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Biology, Hauptman-Woodward Medical Research Institute, 700 Ellicott Street, Buffalo, New York 14203, USA. ghosh@hwi.buffalo.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19129847" target="_blank"〉PubMed〈/a〉
    Keywords: Androgens/*metabolism ; Aromatase/*chemistry/*metabolism ; Catalytic Domain ; Crystallography, X-Ray ; Estrogens/*biosynthesis ; Female ; Humans ; Lipid Bilayers/metabolism ; Models, Molecular ; Placenta/enzymology ; Protein Binding ; Protein Conformation ; Substrate Specificity
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    Cell biology: The proteasome assembly line (2009)
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    Publication Date: 2009-06-12
    Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3808163/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3808163/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Madura, Kiran -- R01 CA083875/CA/NCI NIH HHS/ -- England -- Nature. 2009 Jun 11;459(7248):787-8. doi: 10.1038/459787a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19516331" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/chemistry/*metabolism ; Humans ; Models, Biological ; Molecular Chaperones/*metabolism ; Proteasome Endopeptidase Complex/*biosynthesis/*chemistry/metabolism ; Protein Binding ; Saccharomyces cerevisiae/*enzymology/genetics ; Saccharomyces cerevisiae Proteins/metabolism
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    Structure of the connexin 26 gap junction channel at 3.5 A resolution (2009)
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    Publication Date: 2009-04-03
    Description: Gap junctions consist of arrays of intercellular channels between adjacent cells that permit the exchange of ions and small molecules. Here we report the crystal structure of the gap junction channel formed by human connexin 26 (Cx26, also known as GJB2) at 3.5 A resolution, and discuss structural determinants of solute transport through the channel. The density map showed the two membrane-spanning hemichannels and the arrangement of the four transmembrane helices of the six protomers forming each hemichannel. The hemichannels feature a positively charged cytoplasmic entrance, a funnel, a negatively charged transmembrane pathway, and an extracellular cavity. The pore is narrowed at the funnel, which is formed by the six amino-terminal helices lining the wall of the channel, which thus determines the molecular size restriction at the channel entrance. The structure of the Cx26 gap junction channel also has implications for the gating of the channel by the transjunctional voltage.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Maeda, Shoji -- Nakagawa, So -- Suga, Michihiro -- Yamashita, Eiki -- Oshima, Atsunori -- Fujiyoshi, Yoshinori -- Tsukihara, Tomitake -- England -- Nature. 2009 Apr 2;458(7238):597-602. doi: 10.1038/nature07869.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Protein Research, Osaka University, OLABB, 6-2-3, Furuedai, Suita, Osaka 565-0874, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19340074" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Connexins/*chemistry/genetics ; Crystallography, X-Ray ; Gap Junctions/*chemistry ; Humans ; Ion Channel Gating ; Models, Molecular ; Protein Multimerization ; Protein Structure, Quaternary ; Spodoptera/virology
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    An RNA-dependent RNA polymerase formed by TERT and the RMRP RNA (2009)
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    Publication Date: 2009-08-25
    Description: Constitutive expression of telomerase in human cells prevents the onset of senescence and crisis by maintaining telomere homeostasis. However, accumulating evidence suggests that the human telomerase reverse transcriptase catalytic subunit (TERT) contributes to cell physiology independently of its ability to elongate telomeres. Here we show that TERT interacts with the RNA component of mitochondrial RNA processing endoribonuclease (RMRP), a gene that is mutated in the inherited pleiotropic syndrome cartilage-hair hypoplasia. Human TERT and RMRP form a distinct ribonucleoprotein complex that has RNA-dependent RNA polymerase (RdRP) activity and produces double-stranded RNAs that can be processed into small interfering RNA in a Dicer (also known as DICER1)-dependent manner. These observations identify a mammalian RdRP composed of TERT in complex with RMRP.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755635/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755635/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Maida, Yoshiko -- Yasukawa, Mami -- Furuuchi, Miho -- Lassmann, Timo -- Possemato, Richard -- Okamoto, Naoko -- Kasim, Vivi -- Hayashizaki, Yoshihide -- Hahn, William C -- Masutomi, Kenkichi -- R01 AG023145/AG/NIA NIH HHS/ -- R01 AG023145-05/AG/NIA NIH HHS/ -- R01 AG23145/AG/NIA NIH HHS/ -- England -- Nature. 2009 Sep 10;461(7261):230-5. doi: 10.1038/nature08283. Epub 2009 Aug 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Stem Cell Project, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19701182" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line ; Endoribonucleases/*genetics ; Gene Expression Regulation ; HeLa Cells ; Humans ; Protein Binding ; RNA Replicase/*chemistry/*metabolism ; RNA, Double-Stranded/biosynthesis/genetics/metabolism ; RNA, Long Noncoding ; RNA, Small Interfering/biosynthesis/genetics/metabolism ; RNA, Untranslated/genetics/*metabolism ; Ribonuclease III/deficiency/genetics/metabolism ; Ribonucleoproteins/genetics/*metabolism ; Telomerase/genetics/*metabolism
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    Crystal structure of human spliceosomal U1 snRNP at 5.5 A resolution (2009)
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    Publication Date: 2009-03-28
    Description: Human spliceosomal U1 small nuclear ribonucleoprotein particles (snRNPs), which consist of U1 small nuclear RNA and ten proteins, recognize the 5' splice site within precursor messenger RNAs and initiate the assembly of the spliceosome for intron excision. An electron density map of the functional core of U1 snRNP at 5.5 A resolution has enabled us to build the RNA and, in conjunction with site-specific labelling of individual proteins, to place the seven Sm proteins, U1-C and U1-70K into the map. Here we present the detailed structure of a spliceosomal snRNP, revealing a hierarchical network of intricate interactions between subunits. A striking feature is the amino (N)-terminal polypeptide of U1-70K, which extends over a distance of 180 A from its RNA binding domain, wraps around the core domain consisting of the seven Sm proteins and finally contacts U1-C, which is crucial for 5'-splice-site recognition. The structure of U1 snRNP provides insights into U1 snRNP assembly and suggests a possible mechanism of 5'-splice-site recognition.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673513/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673513/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pomeranz Krummel, Daniel A -- Oubridge, Chris -- Leung, Adelaine K W -- Li, Jade -- Nagai, Kiyoshi -- MC_U105184330/Medical Research Council/United Kingdom -- U.1051.04.016(78933)/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2009 Mar 26;458(7237):475-80. doi: 10.1038/nature07851.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19325628" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Humans ; Models, Biological ; Models, Molecular ; Nucleic Acid Conformation ; Protein Folding ; Protein Structure, Tertiary ; RNA Splice Sites ; RNA Splicing ; RNA, Small Nuclear/chemistry ; Ribonucleoprotein, U1 Small Nuclear/*chemistry/metabolism ; Spliceosomes/*chemistry ; Zinc Fingers
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    X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor (2009)
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    Publication Date: 2009-12-01
    Description: Ionotropic glutamate receptors mediate most excitatory neurotransmission in the central nervous system and function by opening a transmembrane ion channel upon binding of glutamate. Despite their crucial role in neurobiology, the architecture and atomic structure of an intact ionotropic glutamate receptor are unknown. Here we report the crystal structure of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive, homotetrameric, rat GluA2 receptor at 3.6 A resolution in complex with a competitive antagonist. The receptor harbours an overall axis of two-fold symmetry with the extracellular domains organized as pairs of local dimers and with the ion channel domain exhibiting four-fold symmetry. A symmetry mismatch between the extracellular and ion channel domains is mediated by two pairs of conformationally distinct subunits, A/C and B/D. Therefore, the stereochemical manner in which the A/C subunits are coupled to the ion channel gate is different from the B/D subunits. Guided by the GluA2 structure and site-directed cysteine mutagenesis, we suggest that GluN1 and GluN2A NMDA (N-methyl-d-aspartate) receptors have a similar architecture, with subunits arranged in a 1-2-1-2 pattern. We exploit the GluA2 structure to develop mechanisms of ion channel activation, desensitization and inhibition by non-competitive antagonists and pore blockers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861655/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861655/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sobolevsky, Alexander I -- Rosconi, Michael P -- Gouaux, Eric -- F32 NS049767-05/NS/NINDS NIH HHS/ -- R01 NS038631/NS/NINDS NIH HHS/ -- R01 NS038631-06/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Dec 10;462(7274):745-56. doi: 10.1038/nature08624. Epub .〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19946266" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Crystallization ; Crystallography, X-Ray ; Ion Channel Gating ; Models, Molecular ; Potassium Channels/chemistry/metabolism ; Protein Conformation ; Protein Subunits/chemistry/metabolism ; Rats ; Receptors, AMPA/antagonists & inhibitors/*chemistry/*metabolism ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism
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    Role of the polycomb protein EED in the propagation of repressive histone marks (2009)
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    Publication Date: 2009-09-22
    Description: Polycomb group proteins have an essential role in the epigenetic maintenance of repressive chromatin states. The gene-silencing activity of the Polycomb repressive complex 2 (PRC2) depends on its ability to trimethylate lysine 27 of histone H3 (H3K27) by the catalytic SET domain of the EZH2 subunit, and at least two other subunits of the complex: SUZ12 and EED. Here we show that the carboxy-terminal domain of EED specifically binds to histone tails carrying trimethyl-lysine residues associated with repressive chromatin marks, and that this leads to the allosteric activation of the methyltransferase activity of PRC2. Mutations in EED that prevent it from recognizing repressive trimethyl-lysine marks abolish the activation of PRC2 in vitro and, in Drosophila, reduce global methylation and disrupt development. These findings suggest a model for the propagation of the H3K27me3 mark that accounts for the maintenance of repressive chromatin domains and for the transmission of a histone modification from mother to daughter cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772642/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772642/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Margueron, Raphael -- Justin, Neil -- Ohno, Katsuhito -- Sharpe, Miriam L -- Son, Jinsook -- Drury, William J 3rd -- Voigt, Philipp -- Martin, Stephen R -- Taylor, William R -- De Marco, Valeria -- Pirrotta, Vincenzo -- Reinberg, Danny -- Gamblin, Steven J -- GM064844/GM/NIGMS NIH HHS/ -- GM37120/GM/NIGMS NIH HHS/ -- MC_U117584222/Medical Research Council/United Kingdom -- R01 GM064844/GM/NIGMS NIH HHS/ -- R01 GM064844-08/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- Medical Research Council/United Kingdom -- England -- Nature. 2009 Oct 8;461(7265):762-7. doi: 10.1038/nature08398. Epub 2009 Sep 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Biochemistry, New York University Medical School, 522 First Avenue, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19767730" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Animals ; Cell Line ; Chromatin/chemistry/*genetics/metabolism ; Crystallography, X-Ray ; Drosophila Proteins/chemistry/genetics/*metabolism ; Drosophila melanogaster/*genetics/growth & development/*metabolism ; Enzyme Activation ; *Gene Silencing ; Histone-Lysine N-Methyltransferase/chemistry/metabolism ; Histones/*chemistry/*metabolism ; Lysine/analogs & derivatives/metabolism ; Methylation ; Models, Biological ; Models, Molecular ; Nuclear Proteins/metabolism ; Nucleosomes/chemistry/genetics/metabolism ; Polycomb Repressive Complex 2 ; Protein Binding ; Protein Structure, Tertiary ; Repressor Proteins/chemistry/genetics/*metabolism ; Substrate Specificity
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    Structural biology: Tracing Argonaute binding (2009)
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    Publication Date: 2009-10-09
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bouasker, Samir -- Simard, Martin J -- England -- Nature. 2009 Oct 8;461(7265):743-4. doi: 10.1038/461743a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19812664" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Catalytic Domain/genetics ; Crystallography, X-Ray ; DNA/metabolism ; *Gene Silencing ; Magnesium/metabolism ; RNA/*metabolism ; RNA-Induced Silencing Complex/*chemistry/*metabolism ; Thermus thermophilus/*enzymology
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    Encounter and extrusion of an intrahelical lesion by a DNA repair enzyme (2009)
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    Publication Date: 2009-12-17
    Description: How living systems detect the presence of genotoxic damage embedded in a million-fold excess of undamaged DNA is an unresolved question in biology. Here we have captured and structurally elucidated a base-excision DNA repair enzyme, MutM, at the stage of initial encounter with a damaged nucleobase, 8-oxoguanine (oxoG), nested within a DNA duplex. Three structures of intrahelical oxoG-encounter complexes are compared with sequence-matched structures containing a normal G base in place of an oxoG lesion. Although the protein-DNA interfaces in the matched complexes differ by only two atoms-those that distinguish oxoG from G-their pronounced structural differences indicate that MutM can detect a lesion in DNA even at the earliest stages of encounter. All-atom computer simulations show the pathway by which encounter of the enzyme with the lesion causes extrusion from the DNA duplex, and they elucidate the critical free energy difference between oxoG and G along the extrusion pathway.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951314/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951314/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Qi, Yan -- Spong, Marie C -- Nam, Kwangho -- Banerjee, Anirban -- Jiralerspong, Sao -- Karplus, Martin -- Verdine, Gregory L -- CA100742/CA/NCI NIH HHS/ -- GM030804/GM/NIGMS NIH HHS/ -- GM044853/GM/NIGMS NIH HHS/ -- GM047467/GM/NIGMS NIH HHS/ -- P01 GM047467/GM/NIGMS NIH HHS/ -- P01 GM047467-100006/GM/NIGMS NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 CA100742/CA/NCI NIH HHS/ -- R01 CA100742-06A1/CA/NCI NIH HHS/ -- R01 GM044853/GM/NIGMS NIH HHS/ -- R01 GM044853-18/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Dec 10;462(7274):762-6. doi: 10.1038/nature08561.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Graduate Program in Biophysics, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20010681" target="_blank"〉PubMed〈/a〉
    Keywords: Biocatalysis ; Computer Simulation ; Crystallography, X-Ray ; *DNA Damage ; *DNA Repair ; DNA-Formamidopyrimidine Glycosylase/genetics/*metabolism ; Genome, Bacterial/genetics ; Geobacillus stearothermophilus/*enzymology/genetics ; Guanine/*analogs & derivatives/metabolism ; Models, Biological ; Models, Molecular ; Molecular Dynamics Simulation ; Mutation/genetics ; Thermodynamics
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    Embryonic stem cells use ZFP809 to silence retroviral DNAs (2009)
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    Publication Date: 2009-03-10
    Description: Embryonic stem cells (ESCs) and other primitive stem cells of mice have been known for more than 30 years to potently block retrovirus replication. Infection of ESCs by the murine leukaemia viruses (MLVs) results in the normal establishment of integrated proviral DNA, but this DNA is then transcriptionally silenced, preventing further viral spread. The repression is largely mediated by trans-acting factors that recognize a conserved sequence element termed the primer binding site, an 18-base pair sequence complementary to the 3' end of a cellular transfer RNA. A specific tRNA is annealed to the primer binding site sequence of the viral genomic RNA, and is used to prime DNA synthesis. This same sequence in the context of the integrated proviral DNA is targeted for silencing in ESCs. We have recently shown that a large protein complex binding to the primer binding site in ESCs contains TRIM28 (refs 8, 9), a well-characterized transcriptional co-repressor. An important question remains as to the identity of the factor that directly recognizes integrated retroviral DNAs and recruits TRIM28 to mediate their specific silencing. Here we identify the zinc finger protein ZFP809 as the recognition molecule that bridges the integrated proviral DNA and TRIM28. We show that expression of ZFP809 is sufficient to render even differentiated cells highly resistant to MLV infection. Furthermore, we demonstrate that ZFP809 is able to potently block transcription from DNA constructs of human T-cell lymphotropic virus-1 (HTLV-1), which use the same primer tRNA. These results identify ZFP809 as a DNA-binding factor that specifically recognizes a large subset of mammalian retroviruses and retroelements, targeting them for transcriptional silencing. We propose that ZFP809 evolved as a stem-cell-specific retroviral restriction factor, and therefore constitutes a new component of the intrinsic immune system of stem cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2676211/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2676211/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wolf, Daniel -- Goff, Stephen P -- R37 CA 30488/CA/NCI NIH HHS/ -- R37 CA030488/CA/NCI NIH HHS/ -- R37 CA030488-29/CA/NCI NIH HHS/ -- R37 CA030488-30/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Apr 30;458(7242):1201-4. doi: 10.1038/nature07844. Epub 2009 Mar 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, HHSC 1310, 701 West 168th Street, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19270682" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Differentiation ; Cell Line ; DNA, Viral/*genetics/metabolism ; DNA-Binding Proteins/genetics/isolation & purification/*metabolism ; Embryonic Stem Cells/*metabolism/*virology ; *Gene Expression Regulation, Viral ; *Gene Silencing ; Human T-lymphotropic virus 1/genetics/growth & development ; Humans ; Leukemia Virus, Murine/genetics/growth & development ; Mice ; Nuclear Proteins/metabolism ; Protein Binding ; RNA/genetics ; Repressor Proteins/metabolism ; Retroviridae/*genetics/growth & development ; Virus Replication
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    An epistatic ratchet constrains the direction of glucocorticoid receptor evolution (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-09-26
    Description: The extent to which evolution is reversible has long fascinated biologists. Most previous work on the reversibility of morphological and life-history evolution has been indecisive, because of uncertainty and bias in the methods used to infer ancestral states for such characters. Further, despite theoretical work on the factors that could contribute to irreversibility, there is little empirical evidence on its causes, because sufficient understanding of the mechanistic basis for the evolution of new or ancestral phenotypes is seldom available. By studying the reversibility of evolutionary changes in protein structure and function, these limitations can be overcome. Here we show, using the evolution of hormone specificity in the vertebrate glucocorticoid receptor as a case-study, that the evolutionary path by which this protein acquired its new function soon became inaccessible to reverse exploration. Using ancestral gene reconstruction, protein engineering and X-ray crystallography, we demonstrate that five subsequent 'restrictive' mutations, which optimized the new specificity of the glucocorticoid receptor, also destabilized elements of the protein structure that were required to support the ancestral conformation. Unless these ratchet-like epistatic substitutions are restored to their ancestral states, reversing the key function-switching mutations yields a non-functional protein. Reversing the restrictive substitutions first, however, does nothing to enhance the ancestral function. Our findings indicate that even if selection for the ancestral function were imposed, direct reversal would be extremely unlikely, suggesting an important role for historical contingency in protein evolution.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bridgham, Jamie T -- Ortlund, Eric A -- Thornton, Joseph W -- F32-GM074398/GM/NIGMS NIH HHS/ -- R01 GM081592/GM/NIGMS NIH HHS/ -- R01-GM081592/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Sep 24;461(7263):515-9. doi: 10.1038/nature08249.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Ecology and Evolutionary Biology, University of Oregon, Eugene, Oregon 97403, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19779450" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; CHO Cells ; Cricetinae ; Cricetulus ; Crystallography, X-Ray ; Epistasis, Genetic ; *Evolution, Molecular ; Hormones/metabolism ; *Models, Biological ; Models, Molecular ; Mutation/genetics ; Protein Engineering ; Receptors, Glucocorticoid/*chemistry/*genetics/metabolism ; Sequence Alignment ; Substrate Specificity
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Membrane scission by the ESCRT-III complex (2009)
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    Publication Date: 2009-02-24
    Description: The endosomal sorting complex required for transport (ESCRT) system is essential for multivesicular body biogenesis, in which cargo sorting is coupled to the invagination and scission of intralumenal vesicles. The ESCRTs are also needed for budding of enveloped viruses including human immunodeficiency virus 1, and for membrane abscission in cytokinesis. In Saccharomyces cerevisiae, ESCRT-III consists of Vps20, Snf7, Vps24 and Vps2 (also known as Did4), which assemble in that order and require the ATPase Vps4 for their disassembly. In this study, the ESCRT-III-dependent budding and scission of intralumenal vesicles into giant unilamellar vesicles was reconstituted and visualized by fluorescence microscopy. Here we show that three subunits of ESCRT-III, Vps20, Snf7 and Vps24, are sufficient to detach intralumenal vesicles. Vps2, the ESCRT-III subunit responsible for recruiting Vps4, and the ATPase activity of Vps4 were required for ESCRT-III recycling and supported additional rounds of budding. The minimum set of ESCRT-III and Vps4 proteins capable of multiple cycles of vesicle detachment corresponds to the ancient set of ESCRT proteins conserved from archaea to animals.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743992/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743992/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wollert, Thomas -- Wunder, Christian -- Lippincott-Schwartz, Jennifer -- Hurley, James H -- Z01 DK036123-01/Intramural NIH HHS/ -- England -- Nature. 2009 Mar 12;458(7235):172-7. doi: 10.1038/nature07836. Epub 2009 Feb 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19234443" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases ; Adenosine Triphosphate/metabolism ; Cell Division/physiology ; Endosomal Sorting Complexes Required for Transport ; Endosomes/*metabolism ; Intracellular Membranes/metabolism/*physiology ; Protein Binding ; Saccharomyces cerevisiae/*cytology/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Transport Vesicles/*metabolism ; Vesicular Transport Proteins/*metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Neuroscience: Excitatory view of a receptor (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-12-17
    Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225193/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225193/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wollmuth, Lonnie P -- Traynelis, Stephen F -- R01 MH066892/MH/NIMH NIH HHS/ -- R01 MH066892-08/MH/NIMH NIH HHS/ -- England -- Nature. 2009 Dec 10;462(7274):729-31. doi: 10.1038/462729a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20010675" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Crystallography, X-Ray ; Ion Channel Gating ; Models, Molecular ; Protein Conformation ; Protein Subunits/chemistry/metabolism ; Rats ; Receptors, AMPA/antagonists & inhibitors/*chemistry/*metabolism ; Receptors, N-Methyl-D-Aspartate/chemistry/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Rationally tuning the reduction potential of a single cupredoxin beyond the natural range (2009)
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    Publication Date: 2009-11-06
    Description: Redox processes are at the heart of numerous functions in chemistry and biology, from long-range electron transfer in photosynthesis and respiration to catalysis in industrial and fuel cell research. These functions are accomplished in nature by only a limited number of redox-active agents. A long-standing issue in these fields is how redox potentials are fine-tuned over a broad range with little change to the redox-active site or electron-transfer properties. Resolving this issue will not only advance our fundamental understanding of the roles of long-range, non-covalent interactions in redox processes, but also allow for design of redox-active proteins having tailor-made redox potentials for applications such as artificial photosynthetic centres or fuel cell catalysts for energy conversion. Here we show that two important secondary coordination sphere interactions, hydrophobicity and hydrogen-bonding, are capable of tuning the reduction potential of the cupredoxin azurin over a 700 mV range, surpassing the highest and lowest reduction potentials reported for any mononuclear cupredoxin, without perturbing the metal binding site beyond what is typical for the cupredoxin family of proteins. We also demonstrate that the effects of individual structural features are additive and that redox potential tuning of azurin is now predictable across the full range of cupredoxin potentials.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149807/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149807/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Marshall, Nicholas M -- Garner, Dewain K -- Wilson, Tiffany D -- Gao, Yi-Gui -- Robinson, Howard -- Nilges, Mark J -- Lu, Yi -- 5 T32 GM070421/GM/NIGMS NIH HHS/ -- T32 GM070421/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Nov 5;462(7269):113-6. doi: 10.1038/nature08551.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, University of Illinois, Urbana-Champaign, Illinois 61801, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19890331" target="_blank"〉PubMed〈/a〉
    Keywords: Azurin/*chemistry/genetics/*metabolism ; Binding Sites ; Copper/metabolism ; Crystallography, X-Ray ; Hydrogen Bonding ; Hydrophobic and Hydrophilic Interactions ; Models, Molecular ; Mutant Proteins/chemistry/genetics/metabolism ; Mutation ; Oxidation-Reduction ; Protein Conformation
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    Helical extension of the neuronal SNARE complex into the membrane (2009)
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    Publication Date: 2009-07-03
    Description: Neurotransmission relies on synaptic vesicles fusing with the membrane of nerve cells to release their neurotransmitter content into the synaptic cleft, a process requiring the assembly of several members of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) family. SNAREs represent an evolutionarily conserved protein family that mediates membrane fusion in the secretory and endocytic pathways of eukaryotic cells. On membrane contact, these proteins assemble in trans between the membranes as a bundle of four alpha-helices, with the energy released during assembly being thought to drive fusion. However, it is unclear how the energy is transferred to the membranes and whether assembly is conformationally linked to fusion. Here, we report the X-ray structure of the neuronal SNARE complex, consisting of rat syntaxin 1A, SNAP-25 and synaptobrevin 2, with the carboxy-terminal linkers and transmembrane regions at 3.4 A resolution. The structure shows that assembly proceeds beyond the already known core SNARE complex, resulting in a continuous helical bundle that is further stabilized by side-chain interactions in the linker region. Our results suggest that the final phase of SNARE assembly is directly coupled to membrane merger.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108252/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108252/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stein, Alexander -- Weber, Gert -- Wahl, Markus C -- Jahn, Reinhard -- P01 GM072694/GM/NIGMS NIH HHS/ -- P01 GM072694-01/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Jul 23;460(7254):525-8. doi: 10.1038/nature08156. Epub 2009 Jul 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, Max Planck Institute for Biophysical Chemistry, 37077 Gottingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19571812" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Crystallography, X-Ray ; Membrane Proteins/*chemistry ; Mice ; *Models, Molecular ; Neurons/*metabolism ; Protein Stability ; Protein Structure, Quaternary ; Rats ; SNARE Proteins/*chemistry/*metabolism ; Synapses/metabolism ; Syntaxin 1/chemistry ; Transition Temperature ; Vesicle-Associated Membrane Protein 2/chemistry
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Structural biology: Spliceosome subunit revealed (2009)
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    Publication Date: 2009-03-28
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Query, Charles C -- R01 GM057829/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Mar 26;458(7237):418-9. doi: 10.1038/458418a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19325619" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Humans ; Introns/genetics ; Protein Structure, Tertiary ; RNA Splicing ; RNA, Small Nuclear/chemistry ; Ribonucleoprotein, U1 Small Nuclear/*chemistry/genetics/metabolism ; Spliceosomes/*chemistry/genetics/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    A genetically encoded photoactivatable Rac controls the motility of living cells (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-08-21
    Description: The precise spatio-temporal dynamics of protein activity are often critical in determining cell behaviour, yet for most proteins they remain poorly understood; it remains difficult to manipulate protein activity at precise times and places within living cells. Protein activity has been controlled by light, through protein derivatization with photocleavable moieties or using photoreactive small-molecule ligands. However, this requires use of toxic ultraviolet wavelengths, activation is irreversible, and/or cell loading is accomplished via disruption of the cell membrane (for example, through microinjection). Here we have developed a new approach to produce genetically encoded photoactivatable derivatives of Rac1, a key GTPase regulating actin cytoskeletal dynamics in metazoan cells. Rac1 mutants were fused to the photoreactive LOV (light oxygen voltage) domain from phototropin, sterically blocking Rac1 interactions until irradiation unwound a helix linking LOV to Rac1. Photoactivatable Rac1 (PA-Rac1) could be reversibly and repeatedly activated using 458- or 473-nm light to generate precisely localized cell protrusions and ruffling. Localized Rac activation or inactivation was sufficient to produce cell motility and control the direction of cell movement. Myosin was involved in Rac control of directionality but not in Rac-induced protrusion, whereas PAK was required for Rac-induced protrusion. PA-Rac1 was used to elucidate Rac regulation of RhoA in cell motility. Rac and Rho coordinate cytoskeletal behaviours with seconds and submicrometre precision. Their mutual regulation remains controversial, with data indicating that Rac inhibits and/or activates Rho. Rac was shown to inhibit RhoA in mouse embryonic fibroblasts, with inhibition modulated at protrusions and ruffles. A PA-Rac crystal structure and modelling revealed LOV-Rac interactions that will facilitate extension of this photoactivation approach to other proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2766670/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2766670/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wu, Yi I -- Frey, Daniel -- Lungu, Oana I -- Jaehrig, Angelika -- Schlichting, Ilme -- Kuhlman, Brian -- Hahn, Klaus M -- GM057464/GM/NIGMS NIH HHS/ -- GM64346/GM/NIGMS NIH HHS/ -- R01 GM057464/GM/NIGMS NIH HHS/ -- R01 GM057464-09/GM/NIGMS NIH HHS/ -- U54 GM064346/GM/NIGMS NIH HHS/ -- U54 GM064346-089026/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Sep 3;461(7260):104-8. doi: 10.1038/nature08241. Epub 2009 Aug 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, USA. yiwu@med.unc.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19693014" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Avena/genetics ; Cell Line ; *Cell Movement/radiation effects ; Cell Surface Extensions ; Cell Survival ; Cryptochromes ; Crystallization ; Crystallography, X-Ray ; Embryo, Mammalian/cytology ; Enzyme Activation/radiation effects ; Fibroblasts ; Flavoproteins/chemistry/genetics/metabolism ; Fluorescence Recovery After Photobleaching ; Genetic Engineering/*methods ; HeLa Cells ; Humans ; Mice ; Models, Molecular ; Myosins/metabolism ; Protein Conformation ; rac1 GTP-Binding Protein/chemistry/*genetics/*metabolism/radiation effects ; rho GTP-Binding Proteins/antagonists & inhibitors/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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