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  • 1
    Publication Date: 2010-09-17
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Feng, Jian -- England -- Nature. 2010 Sep 16;467(7313):271. doi: 10.1038/467271a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20844517" target="_blank"〉PubMed〈/a〉
    Keywords: Embryo Research/economics/ethics/*legislation & jurisprudence ; *Embryonic Stem Cells ; *Federal Government ; Financing, Government/*legislation & jurisprudence ; Humans ; *Religion and Science ; Research Support as Topic/*legislation & jurisprudence ; United States ; Zygote/cytology
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  • 2
    Publication Date: 2010-10-15
    Description: The pre-T-cell antigen receptor (pre-TCR), expressed by immature thymocytes, has a pivotal role in early T-cell development, including TCR beta-selection, survival and proliferation of CD4(-)CD8(-) double-negative thymocytes, and subsequent alphabeta T-cell lineage differentiation. Whereas alphabetaTCR ligation by the peptide-loaded major histocompatibility complex initiates T-cell signalling, pre-TCR-induced signalling occurs by means of a ligand-independent dimerization event. The pre-TCR comprises an invariant alpha-chain (pre-Talpha) that pairs with any TCR beta-chain (TCRbeta) following successful TCR beta-gene rearrangement. Here we provide the basis of pre-Talpha-TCRbeta assembly and pre-TCR dimerization. The pre-Talpha chain comprised a single immunoglobulin-like domain that is structurally distinct from the constant (C) domain of the TCR alpha-chain; nevertheless, the mode of association between pre-Talpha and TCRbeta mirrored that mediated by the Calpha-Cbeta domains of the alphabetaTCR. The pre-TCR had a propensity to dimerize in solution, and the molecular envelope of the pre-TCR dimer correlated well with the observed head-to-tail pre-TCR dimer. This mode of pre-TCR dimerization enabled the pre-Talpha domain to interact with the variable (V) beta domain through residues that are highly conserved across the Vbeta and joining (J) beta gene families, thus mimicking the interactions at the core of the alphabetaTCR's Valpha-Vbeta interface. Disruption of this pre-Talpha-Vbeta dimer interface abrogated pre-TCR dimerization in solution and impaired pre-TCR expression on the cell surface. Accordingly, we provide a mechanism of pre-TCR self-association that allows the pre-Talpha chain to simultaneously 'sample' the correct folding of both the V and C domains of any TCR beta-chain, regardless of its ultimate specificity, which represents a critical checkpoint in T-cell development. This unusual dual-chaperone-like sensing function of pre-Talpha represents a unique mechanism in nature whereby developmental quality control regulates the expression and signalling of an integral membrane receptor complex.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pang, Siew Siew -- Berry, Richard -- Chen, Zhenjun -- Kjer-Nielsen, Lars -- Perugini, Matthew A -- King, Glenn F -- Wang, Christina -- Chew, Sock Hui -- La Gruta, Nicole L -- Williams, Neal K -- Beddoe, Travis -- Tiganis, Tony -- Cowieson, Nathan P -- Godfrey, Dale I -- Purcell, Anthony W -- Wilce, Matthew C J -- McCluskey, James -- Rossjohn, Jamie -- England -- Nature. 2010 Oct 14;467(7317):844-8. doi: 10.1038/nature09448.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20944746" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Gene Rearrangement, T-Lymphocyte/genetics ; Humans ; Models, Molecular ; Mutation ; Protein Folding ; *Protein Multimerization ; Protein Structure, Tertiary ; Receptors, Antigen, T-Cell/*chemistry/genetics/*metabolism ; Receptors, Antigen, T-Cell, alpha-beta/chemistry/metabolism ; Signal Transduction ; Solutions ; T-Lymphocytes/cytology/immunology/metabolism
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  • 3
    Publication Date: 2010-05-21
    Description: MyD88, IRAK4 and IRAK2 are critical signalling mediators of the TLR/IL1-R superfamily. Here we report the crystal structure of the MyD88-IRAK4-IRAK2 death domain (DD) complex, which surprisingly reveals a left-handed helical oligomer that consists of 6 MyD88, 4 IRAK4 and 4 IRAK2 DDs. Assembly of this helical signalling tower is hierarchical, in which MyD88 recruits IRAK4 and the MyD88-IRAK4 complex recruits the IRAK4 substrates IRAK2 or the related IRAK1. Formation of these Myddosome complexes brings the kinase domains of IRAKs into proximity for phosphorylation and activation. Composite binding sites are required for recruitment of the individual DDs in the complex, which are confirmed by mutagenesis and previously identified signalling mutations. Specificities in Myddosome formation are dictated by both molecular complementarity and correspondence of surface electrostatics. The MyD88-IRAK4-IRAK2 complex provides a template for Toll signalling in Drosophila and an elegant mechanism for versatile assembly and regulation of DD complexes in signal transduction.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2888693/" 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/PMC2888693/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lin, Su-Chang -- Lo, Yu-Chih -- Wu, Hao -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 AI050872/AI/NIAID NIH HHS/ -- R01 AI050872-09/AI/NIAID NIH HHS/ -- England -- Nature. 2010 Jun 17;465(7300):885-90. doi: 10.1038/nature09121. Epub 2010 May 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Weill Cornell Medical College, New York, New York 10021, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20485341" target="_blank"〉PubMed〈/a〉
    Keywords: Humans ; *Interleukin-1 Receptor-Associated Kinases/chemistry/metabolism ; *Models, Molecular ; *Myeloid Differentiation Factor 88/chemistry/metabolism ; Protein Structure, Tertiary ; Receptors, Interleukin-1/metabolism/*physiology ; *Signal Transduction ; Toll-Like Receptors/metabolism/*physiology
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  • 4
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    Nature Publishing Group (NPG)
    Publication Date: 2010-09-25
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2010 Sep 23;467(7314):368. doi: 10.1038/467368a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20864950" target="_blank"〉PubMed〈/a〉
    Keywords: Agriculture/*methods ; Animals ; Cattle ; Disease Reservoirs/microbiology/*statistics & numerical data/*veterinary ; *Federal Government ; Great Britain/epidemiology ; *Mustelidae/microbiology ; Reproducibility of Results ; Tuberculosis Vaccines ; Tuberculosis, Bovine/epidemiology/*prevention & control/transmission ; Vaccination/veterinary
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  • 5
    Publication Date: 2010-01-16
    Description: Form I Rubisco (ribulose 1,5-bisphosphate carboxylase/oxygenase), a complex of eight large (RbcL) and eight small (RbcS) subunits, catalyses the fixation of atmospheric CO(2) in photosynthesis. The limited catalytic efficiency of Rubisco has sparked extensive efforts to re-engineer the enzyme with the goal of enhancing agricultural productivity. To facilitate such efforts we analysed the formation of cyanobacterial form I Rubisco by in vitro reconstitution and cryo-electron microscopy. We show that RbcL subunit folding by the GroEL/GroES chaperonin is tightly coupled with assembly mediated by the chaperone RbcX(2). RbcL monomers remain partially unstable and retain high affinity for GroEL until captured by RbcX(2). As revealed by the structure of a RbcL(8)-(RbcX(2))(8) assembly intermediate, RbcX(2) acts as a molecular staple in stabilizing the RbcL subunits as dimers and facilitates RbcL(8) core assembly. Finally, addition of RbcS results in RbcX(2) release and holoenzyme formation. Specific assembly chaperones may be required more generally in the formation of complex oligomeric structures when folding is closely coupled to assembly.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Cuimin -- Young, Anna L -- Starling-Windhof, Amanda -- Bracher, Andreas -- Saschenbrecker, Sandra -- Rao, Bharathi Vasudeva -- Rao, Karnam Vasudeva -- Berninghausen, Otto -- Mielke, Thorsten -- Hartl, F Ulrich -- Beckmann, Roland -- Hayer-Hartl, Manajit -- England -- Nature. 2010 Jan 14;463(7278):197-202. doi: 10.1038/nature08651.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20075914" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/chemistry/metabolism ; Chaperonin 10/metabolism ; Chaperonin 60/metabolism ; Cryoelectron Microscopy ; Holoenzymes/chemistry/metabolism ; Models, Molecular ; Molecular Chaperones/chemistry/*metabolism ; Protein Binding ; *Protein Folding ; *Protein Multimerization ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Ribulose-Bisphosphate Carboxylase/*chemistry/*metabolism/ultrastructure ; Synechococcus/*chemistry/metabolism
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  • 6
    Publication Date: 2010-05-25
    Description: The three-dimensional structures of proteins often show a modular architecture comprised of discrete structural regions or domains. Cooperative communication between these regions is important for catalysis, regulation and efficient folding; lack of coupling has been implicated in the formation of fibrils and other misfolding pathologies. How different structural regions of a protein communicate and contribute to a protein's overall energetics and folding, however, is still poorly understood. Here we use a single-molecule optical tweezers approach to induce the selective unfolding of particular regions of T4 lysozyme and monitor the effect on other regions not directly acted on by force. We investigate how the topological organization of a protein (the order of structural elements along the sequence) affects the coupling and folding cooperativity between its domains. To probe the status of the regions not directly subjected to force, we determine the free energy changes during mechanical unfolding using Crooks' fluctuation theorem. We pull on topological variants (circular permutants) and find that the topological organization of the polypeptide chain critically determines the folding cooperativity between domains and thus what parts of the folding/unfolding landscape are explored. We speculate that proteins may have evolved to select certain topologies that increase coupling between regions to avoid areas of the landscape that lead to kinetic trapping and misfolding.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911970/" 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/PMC2911970/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shank, Elizabeth A -- Cecconi, Ciro -- Dill, Jesse W -- Marqusee, Susan -- Bustamante, Carlos -- GM 32543/GM/NIGMS NIH HHS/ -- GM 50945/GM/NIGMS NIH HHS/ -- R01 GM050945/GM/NIGMS NIH HHS/ -- R01 GM050945-17/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Jun 3;465(7298):637-40. doi: 10.1038/nature09021. Epub 2010 May 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular & Cell Biology, University of California, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20495548" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Bacteriophage T4/*enzymology ; Models, Molecular ; Mutant Proteins/chemistry/genetics/metabolism ; Optical Tweezers ; Probability ; Protein Denaturation ; *Protein Folding ; Protein Structure, Tertiary ; Viral Proteins/*chemistry/genetics/*metabolism
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  • 7
    Publication Date: 2010-02-09
    Description: Ca(2+) channels and calmodulin (CaM) are two prominent signalling hubs that synergistically affect functions as diverse as cardiac excitability, synaptic plasticity and gene transcription. It is therefore fitting that these hubs are in some sense coordinated, as the opening of Ca(V)1-2 Ca(2+) channels are regulated by a single CaM constitutively complexed with channels. The Ca(2+)-free form of CaM (apoCaM) is already pre-associated with the isoleucine-glutamine (IQ) domain on the channel carboxy terminus, and subsequent Ca(2+) binding to this 'resident' CaM drives conformational changes that then trigger regulation of channel opening. Another potential avenue for channel-CaM coordination could arise from the absence of Ca(2+) regulation in channels lacking a pre-associated CaM. Natural fluctuations in CaM concentrations might then influence the fraction of regulable channels and, thereby, the overall strength of Ca(2+) feedback. However, the prevailing view has been that the ultrastrong affinity of channels for apoCaM ensures their saturation with CaM, yielding a significant form of concentration independence between Ca(2+) channels and CaM. Here we show that significant exceptions to this autonomy exist, by combining electrophysiology (to characterize channel regulation) with optical fluorescence resonance energy transfer (FRET) sensor determination of free-apoCaM concentration in live cells. This approach translates quantitative CaM biochemistry from the traditional test-tube context into the realm of functioning holochannels within intact cells. From this perspective, we find that long splice forms of Ca(V)1.3 and Ca(V)1.4 channels include a distal carboxy tail that resembles an enzyme competitive inhibitor that retunes channel affinity for apoCaM such that natural CaM variations affect the strength of Ca(2+) feedback modulation. Given the ubiquity of these channels, the connection between ambient CaM levels and Ca(2+) entry through channels is broadly significant for Ca(2+) homeostasis. Strategies such as ours promise key advances for the in situ analysis of signalling molecules resistant to in vitro reconstitution, such as Ca(2+) channels.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553577/" 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/PMC3553577/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Xiaodong -- Yang, Philemon S -- Yang, Wanjun -- Yue, David T -- P30 DC005211/DC/NIDCD NIH HHS/ -- R01 DC000276/DC/NIDCD NIH HHS/ -- England -- Nature. 2010 Feb 18;463(7283):968-72. doi: 10.1038/nature08766. Epub 2010 Feb 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Calcium Signals Laboratory, Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Ross Building, Room 713, 720 Rutland Avenue, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20139964" target="_blank"〉PubMed〈/a〉
    Keywords: Alternative Splicing ; Animals ; Apoproteins/analysis/metabolism ; Binding, Competitive/drug effects ; Calcium/analysis/metabolism/pharmacology ; Calcium Channel Blockers/*chemistry/*metabolism ; Calcium Channels/*chemistry/genetics/*metabolism ; Calmodulin/analysis/*metabolism ; Cell Line ; Cell Survival ; Electrophysiology ; *Feedback, Physiological ; Fluorescence Resonance Energy Transfer ; Humans ; Protein Structure, Tertiary ; Rats ; Recombinant Fusion Proteins/chemistry/genetics/metabolism
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  • 8
    Publication Date: 2010-12-24
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bernado, Pau -- Blackledge, Martin -- England -- Nature. 2010 Dec 23;468(7327):1046-8. doi: 10.1038/4681046a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21179158" target="_blank"〉PubMed〈/a〉
    Keywords: *Biochemistry/methods ; Models, Chemical ; Protein Structure, Tertiary ; Proteins/*chemistry ; Proto-Oncogene Proteins c-hck/chemistry
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  • 9
    Publication Date: 2010-10-12
    Description: Jasmonates are a family of plant hormones that regulate plant growth, development and responses to stress. The F-box protein CORONATINE INSENSITIVE 1 (COI1) mediates jasmonate signalling by promoting hormone-dependent ubiquitylation and degradation of transcriptional repressor JAZ proteins. Despite its importance, the mechanism of jasmonate perception remains unclear. Here we present structural and pharmacological data to show that the true Arabidopsis jasmonate receptor is a complex of both COI1 and JAZ. COI1 contains an open pocket that recognizes the bioactive hormone (3R,7S)-jasmonoyl-l-isoleucine (JA-Ile) with high specificity. High-affinity hormone binding requires a bipartite JAZ degron sequence consisting of a conserved alpha-helix for COI1 docking and a loop region to trap the hormone in its binding pocket. In addition, we identify a third critical component of the jasmonate co-receptor complex, inositol pentakisphosphate, which interacts with both COI1 and JAZ adjacent to the ligand. Our results unravel the mechanism of jasmonate perception and highlight the ability of F-box proteins to evolve as multi-component signalling hubs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988090/" 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/PMC2988090/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sheard, Laura B -- Tan, Xu -- Mao, Haibin -- Withers, John -- Ben-Nissan, Gili -- Hinds, Thomas R -- Kobayashi, Yuichi -- Hsu, Fong-Fu -- Sharon, Michal -- Browse, John -- He, Sheng Yang -- Rizo, Josep -- Howe, Gregg A -- Zheng, Ning -- P30 DK056341/DK/NIDDK NIH HHS/ -- P30 DK056341-10/DK/NIDDK NIH HHS/ -- R01 AI068718/AI/NIAID NIH HHS/ -- R01 AI068718-04/AI/NIAID NIH HHS/ -- R01 CA107134/CA/NCI NIH HHS/ -- R01 CA107134-07/CA/NCI NIH HHS/ -- R01 GM057795/GM/NIGMS NIH HHS/ -- R01 GM057795-12/GM/NIGMS NIH HHS/ -- R01AI068718/AI/NIAID NIH HHS/ -- R01GM57795/GM/NIGMS NIH HHS/ -- T32 GM07270/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Nov 18;468(7322):400-5. doi: 10.1038/nature09430. Epub 2010 Oct 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, Box 357280, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20927106" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Amino Acids/chemistry/metabolism ; Arabidopsis/chemistry/metabolism ; Arabidopsis Proteins/*chemistry/*metabolism ; Binding Sites ; Crystallography, X-Ray ; Cyclopentanes/chemistry/*metabolism ; F-Box Proteins/chemistry/metabolism ; Indenes/chemistry/metabolism ; Inositol Phosphates/*metabolism ; Isoleucine/analogs & derivatives/chemistry/metabolism ; Models, Molecular ; Molecular Sequence Data ; Oxylipins/chemistry/*metabolism ; Peptide Fragments/chemistry/metabolism ; Plant Growth Regulators/chemistry/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Repressor Proteins/*chemistry/*metabolism ; Signal Transduction
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  • 10
    Publication Date: 2010-06-26
    Description: DNA polymerase eta (Poleta) is unique among eukaryotic polymerases in its proficient ability for error-free replication through ultraviolet-induced cyclobutane pyrimidine dimers, and inactivation of Poleta (also known as POLH) in humans causes the variant form of xeroderma pigmentosum (XPV). We present the crystal structures of Saccharomyces cerevisiae Poleta (also known as RAD30) in ternary complex with a cis-syn thymine-thymine (T-T) dimer and with undamaged DNA. The structures reveal that the ability of Poleta to replicate efficiently through the ultraviolet-induced lesion derives from a simple and yet elegant mechanism, wherein the two Ts of the T-T dimer are accommodated in an active site cleft that is much more open than in other polymerases. We also show by structural, biochemical and genetic analysis that the two Ts are maintained in a stable configuration in the active site via interactions with Gln 55, Arg 73 and Met 74. Together, these features define the basis for Poleta's action on ultraviolet-damaged DNA that is crucial in suppressing the mutagenic and carcinogenic consequences of sun exposure, thereby reducing the incidence of skin cancers in humans.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3030469/" 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/PMC3030469/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Silverstein, Timothy D -- Johnson, Robert E -- Jain, Rinku -- Prakash, Louise -- Prakash, Satya -- Aggarwal, Aneel K -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 CA107650/CA/NCI NIH HHS/ -- R01 CA107650-39/CA/NCI NIH HHS/ -- R01 ES017767/ES/NIEHS NIH HHS/ -- R01 ES017767-01/ES/NIEHS NIH HHS/ -- England -- Nature. 2010 Jun 24;465(7301):1039-43. doi: 10.1038/nature09104.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Structural and Chemical Biology, Mount Sinai School of Medicine, Box 1677, 1425 Madison Avenue, New York, New York 10029, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20577207" target="_blank"〉PubMed〈/a〉
    Keywords: Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; DNA/chemistry/metabolism ; DNA Damage ; DNA-Directed DNA Polymerase/*chemistry/genetics/*metabolism ; Humans ; Kinetics ; Models, Molecular ; Mutation, Missense ; Nucleic Acid Conformation ; Protein Structure, Tertiary ; Pyrimidine Dimers/chemistry/metabolism ; Saccharomyces cerevisiae/*enzymology/genetics ; Skin Neoplasms/*enzymology/genetics ; Structure-Activity Relationship ; Xeroderma Pigmentosum/enzymology/genetics
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  • 11
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    Nature Publishing Group (NPG)
    Publication Date: 2010-02-26
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Qiu, Jane -- England -- Nature. 2010 Feb 25;463(7284):1012-3. doi: 10.1038/4631012a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20182485" target="_blank"〉PubMed〈/a〉
    Keywords: China ; Data Collection ; *Federal Government ; Internet/legislation & jurisprudence/utilization ; *Research Personnel ; Search Engine/*legislation & jurisprudence/*utilization
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  • 12
    Publication Date: 2010-08-10
    Description: Mitochondrial calcium uptake has a central role in cell physiology by stimulating ATP production, shaping cytosolic calcium transients and regulating cell death. The biophysical properties of mitochondrial calcium uptake have been studied in detail, but the underlying proteins remain elusive. Here we use an integrative strategy to predict human genes involved in mitochondrial calcium entry based on clues from comparative physiology, evolutionary genomics and organelle proteomics. RNA interference against 13 top candidates highlighted one gene, CBARA1, that we call hereafter mitochondrial calcium uptake 1 (MICU1). Silencing MICU1 does not disrupt mitochondrial respiration or membrane potential but abolishes mitochondrial calcium entry in intact and permeabilized cells, and attenuates the metabolic coupling between cytosolic calcium transients and activation of matrix dehydrogenases. MICU1 is associated with the mitochondrial inner membrane and has two canonical EF hands that are essential for its activity, indicating a role in calcium sensing. MICU1 represents the founding member of a set of proteins required for high-capacity mitochondrial calcium uptake. Its discovery may lead to the complete molecular characterization of mitochondrial calcium uptake pathways, and offers genetic strategies for understanding their contribution to normal physiology and disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2977980/" 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/PMC2977980/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Perocchi, Fabiana -- Gohil, Vishal M -- Girgis, Hany S -- Bao, X Robert -- McCombs, Janet E -- Palmer, Amy E -- Mootha, Vamsi K -- DK080261/DK/NIDDK NIH HHS/ -- GM0077465/GM/NIGMS NIH HHS/ -- GM084027/GM/NIGMS NIH HHS/ -- R01 GM077465/GM/NIGMS NIH HHS/ -- R01 GM077465-01A1/GM/NIGMS NIH HHS/ -- R01 GM077465-02/GM/NIGMS NIH HHS/ -- R01 GM077465-03/GM/NIGMS NIH HHS/ -- R01 GM077465-04/GM/NIGMS NIH HHS/ -- R01 GM077465-05/GM/NIGMS NIH HHS/ -- R01 GM077465-06/GM/NIGMS NIH HHS/ -- R01 GM084027/GM/NIGMS NIH HHS/ -- R24 DK080261/DK/NIDDK NIH HHS/ -- R24 DK080261-04/DK/NIDDK NIH HHS/ -- TR2 GM08759/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Sep 16;467(7313):291-6. doi: 10.1038/nature09358. Epub 2010 Aug 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20693986" target="_blank"〉PubMed〈/a〉
    Keywords: Allergens/*chemistry/genetics/*metabolism ; Amino Acid Sequence ; Antigens, Plant ; Calcium/*metabolism ; *Calcium Signaling ; Calcium-Binding Proteins/*chemistry/deficiency/genetics/*metabolism ; Cation Transport Proteins ; Cell Respiration ; Cytoplasm/metabolism ; DNA, Mitochondrial/analysis ; *EF Hand Motifs ; Endoplasmic Reticulum/metabolism ; Gene Knockdown Techniques ; HeLa Cells ; Homeostasis ; Humans ; Membrane Potentials ; Mitochondria/*metabolism ; Mitochondrial Membrane Transport Proteins ; Mitochondrial Proteins/*chemistry/deficiency/genetics/*metabolism ; NAD/metabolism ; NADP/metabolism ; Oxidative Phosphorylation ; Protein Structure, Tertiary ; Protein Transport ; RNA Interference
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  • 13
    Publication Date: 2010-10-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tollefson, Jeff -- England -- Nature. 2010 Oct 14;467(7317):762. doi: 10.1038/467762a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20944703" target="_blank"〉PubMed〈/a〉
    Keywords: Conservation of Energy Resources/legislation & jurisprudence ; Environmental Policy/*legislation & jurisprudence ; *Federal Government ; Global Warming/*legislation & jurisprudence/prevention & control ; *Politics ; United States
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  • 14
    Publication Date: 2010-01-30
    Description: Vitamin K epoxide reductase (VKOR) generates vitamin K hydroquinone to sustain gamma-carboxylation of many blood coagulation factors. Here, we report the 3.6 A crystal structure of a bacterial homologue of VKOR from Synechococcus sp. The structure shows VKOR in complex with its naturally fused redox partner, a thioredoxin-like domain, and corresponds to an arrested state of electron transfer. The catalytic core of VKOR is a four transmembrane helix bundle that surrounds a quinone, connected through an additional transmembrane segment with the periplasmic thioredoxin-like domain. We propose a pathway for how VKOR uses electrons from cysteines of newly synthesized proteins to reduce a quinone, a mechanism confirmed by in vitro reconstitution of vitamin K-dependent disulphide bridge formation. Our results have implications for the mechanism of the mammalian VKOR and explain how mutations can cause resistance to the VKOR inhibitor warfarin, the most commonly used oral anticoagulant.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919313/" 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/PMC2919313/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Weikai -- Schulman, Sol -- Dutton, Rachel J -- Boyd, Dana -- Beckwith, Jon -- Rapoport, Tom A -- GMO41883/PHS HHS/ -- K99 HL097083/HL/NHLBI NIH HHS/ -- K99 HL097083-01/HL/NHLBI NIH HHS/ -- K991K99HL097083/HL/NHLBI NIH HHS/ -- R00 HL097083/HL/NHLBI NIH HHS/ -- R01 GM041883/GM/NIGMS NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Jan 28;463(7280):507-12. doi: 10.1038/nature08720.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA. weikai@crystal.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20110994" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anticoagulants ; Bacterial Proteins/chemistry ; Catalytic Domain ; Disulfides/chemistry ; Drug Resistance/genetics ; Electron Transport ; Humans ; Membrane Proteins/chemistry ; Mixed Function Oxygenases/*chemistry/genetics ; *Models, Molecular ; Protein Structure, Tertiary ; Synechococcus/*enzymology ; Vitamin K Epoxide Reductases ; Warfarin
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  • 15
    Publication Date: 2010-10-01
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉O'Hara, Kathryn -- England -- Nature. 2010 Sep 30;467(7315):501. doi: 10.1038/467501a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Carleton University. kathryn_ohara@carleton.ca〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20881970" target="_blank"〉PubMed〈/a〉
    Keywords: *Access to Information ; Animals ; Canada ; *Communication ; *Federal Government ; *Freedom ; Global Warming ; Humans ; *Journalism ; Mass Media ; Policy Making ; Politics ; Public Sector ; *Research Personnel
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  • 16
    Publication Date: 2010-09-25
    Description: Gram-negative bacteria, such as Escherichia coli, frequently use tripartite efflux complexes in the resistance-nodulation-cell division (RND) family to expel various toxic compounds from the cell. The efflux system CusCBA is responsible for extruding biocidal Cu(I) and Ag(I) ions. No previous structural information was available for the heavy-metal efflux (HME) subfamily of the RND efflux pumps. Here we describe the crystal structures of the inner-membrane transporter CusA in the absence and presence of bound Cu(I) or Ag(I). These CusA structures provide new structural information about the HME subfamily of RND efflux pumps. The structures suggest that the metal-binding sites, formed by a three-methionine cluster, are located within the cleft region of the periplasmic domain. This cleft is closed in the apo-CusA form but open in the CusA-Cu(I) and CusA-Ag(I) structures, which directly suggests a plausible pathway for ion export. Binding of Cu(I) and Ag(I) triggers significant conformational changes in both the periplasmic and transmembrane domains. The crystal structure indicates that CusA has, in addition to the three-methionine metal-binding site, four methionine pairs-three located in the transmembrane region and one in the periplasmic domain. Genetic analysis and transport assays suggest that CusA is capable of actively picking up metal ions from the cytosol, using these methionine pairs or clusters to bind and export metal ions. These structures suggest a stepwise shuttle mechanism for transport between these sites.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946090/" 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/PMC2946090/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Long, Feng -- Su, Chih-Chia -- Zimmermann, Michael T -- Boyken, Scott E -- Rajashankar, Kanagalaghatta R -- Jernigan, Robert L -- Yu, Edward W -- GM 072014/GM/NIGMS NIH HHS/ -- GM 074027/GM/NIGMS NIH HHS/ -- GM 081680/GM/NIGMS NIH HHS/ -- GM 086431/GM/NIGMS NIH HHS/ -- R01 GM072014/GM/NIGMS NIH HHS/ -- R01 GM074027/GM/NIGMS NIH HHS/ -- R01 GM074027-05/GM/NIGMS NIH HHS/ -- R01 GM086431/GM/NIGMS NIH HHS/ -- R01 GM086431-01A2/GM/NIGMS NIH HHS/ -- RR-15301/RR/NCRR NIH HHS/ -- England -- Nature. 2010 Sep 23;467(7314):484-8. doi: 10.1038/nature09395.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular, Cellular and Developmental Biology Interdepartmental Graduate Program, Iowa State University, Iowa 50011, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20865003" target="_blank"〉PubMed〈/a〉
    Keywords: Apoproteins/chemistry/metabolism ; Binding Sites ; Cell Membrane/metabolism ; Copper/chemistry/*metabolism ; Crystallography, X-Ray ; Cytosol/metabolism ; Escherichia coli/*chemistry ; Escherichia coli Proteins/*chemistry/*metabolism ; Ion Transport ; Membrane Transport Proteins/*chemistry/*metabolism ; Methionine/*metabolism ; Models, Biological ; Models, Molecular ; Periplasm/metabolism ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Silver/chemistry/*metabolism ; Structure-Activity Relationship
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  • 17
    Publication Date: 2010-09-30
    Description: Cell-cell signalling of semaphorin ligands through interaction with plexin receptors is important for the homeostasis and morphogenesis of many tissues and is widely studied for its role in neural connectivity, cancer, cell migration and immune responses. SEMA4D and Sema6A exemplify two diverse vertebrate, membrane-spanning semaphorin classes (4 and 6) that are capable of direct signalling through members of the two largest plexin classes, B and A, respectively. In the absence of any structural information on the plexin ectodomain or its interaction with semaphorins the extracellular specificity and mechanism controlling plexin signalling has remained unresolved. Here we present crystal structures of cognate complexes of the semaphorin-binding regions of plexins B1 and A2 with semaphorin ectodomains (human PLXNB1(1-2)-SEMA4D(ecto) and murine PlxnA2(1-4)-Sema6A(ecto)), plus unliganded structures of PlxnA2(1-4) and Sema6A(ecto). These structures, together with biophysical and cellular assays of wild-type and mutant proteins, reveal that semaphorin dimers independently bind two plexin molecules and that signalling is critically dependent on the avidity of the resulting bivalent 2:2 complex (monomeric semaphorin binds plexin but fails to trigger signalling). In combination, our data favour a cell-cell signalling mechanism involving semaphorin-stabilized plexin dimerization, possibly followed by clustering, which is consistent with previous functional data. Furthermore, the shared generic architecture of the complexes, formed through conserved contacts of the amino-terminal seven-bladed beta-propeller (sema) domains of both semaphorin and plexin, suggests that a common mode of interaction triggers all semaphorin-plexin based signalling, while distinct insertions within or between blades of the sema domains determine binding specificity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587840/" 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/PMC3587840/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Janssen, Bert J C -- Robinson, Ross A -- Perez-Branguli, Francesc -- Bell, Christian H -- Mitchell, Kevin J -- Siebold, Christian -- Jones, E Yvonne -- 082301/Wellcome Trust/United Kingdom -- 083111/Wellcome Trust/United Kingdom -- 10976/Cancer Research UK/United Kingdom -- A10976/Cancer Research UK/United Kingdom -- A3964/Cancer Research UK/United Kingdom -- A5261/Cancer Research UK/United Kingdom -- G0700232/Medical Research Council/United Kingdom -- G0700232(82098)/Medical Research Council/United Kingdom -- G0900084/Medical Research Council/United Kingdom -- G9900061/Medical Research Council/United Kingdom -- G9900061(69203)/Medical Research Council/United Kingdom -- Cancer Research UK/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2010 Oct 28;467(7319):1118-22. doi: 10.1038/nature09468. Epub 2010 Sep 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20877282" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD/chemistry/genetics/metabolism ; Binding Sites ; Cell Adhesion Molecules/*chemistry/genetics/*metabolism ; Cell Communication ; Crystallography, X-Ray ; Humans ; Ligands ; Mice ; Mice, Inbred C57BL ; Models, Molecular ; NIH 3T3 Cells ; Nerve Tissue Proteins/*chemistry/genetics/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Receptors, Cell Surface/chemistry/genetics/metabolism ; Semaphorins/*chemistry/genetics/*metabolism ; *Signal Transduction ; Structure-Activity Relationship
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  • 18
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    Nature Publishing Group (NPG)
    Publication Date: 2010-09-25
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Inouye, David W -- England -- Nature. 2010 Sep 23;467(7314):400. doi: 10.1038/467400c.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20864979" target="_blank"〉PubMed〈/a〉
    Keywords: American Recovery and Reinvestment Act/*economics ; *Federal Government ; Flowers/classification/physiology ; Peer Review, Research/*standards ; United States
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  • 19
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    Nature Publishing Group (NPG)
    Publication Date: 2010-06-04
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tollefson, Jeff -- England -- Nature. 2010 Jun 3;465(7298):535. doi: 10.1038/465535a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20520681" target="_blank"〉PubMed〈/a〉
    Keywords: Advisory Committees ; Disaster Planning/*organization & administration ; Ecosystem ; *Federal Government ; Fires ; Global Warming/*statistics & numerical data ; Public Policy/*legislation & jurisprudence ; *Social Planning ; United States ; Water Supply
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  • 20
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    Nature Publishing Group (NPG)
    Publication Date: 2010-10-01
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2010 Sep 30;467(7315):500. doi: 10.1038/467500a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20881969" target="_blank"〉PubMed〈/a〉
    Keywords: Advisory Committees/*economics/*organization & administration ; *Federal Government ; Great Britain ; Lobbying ; Organizations/*economics/*organization & administration ; Public Sector
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  • 21
    Publication Date: 2010-11-05
    Description: Many physiological events require transient increases in cytosolic Ca(2+) concentrations. Ryanodine receptors (RyRs) are ion channels that govern the release of Ca(2+) from the endoplasmic and sarcoplasmic reticulum. Mutations in RyRs can lead to severe genetic conditions that affect both cardiac and skeletal muscle, but locating the mutated residues in the full-length channel structure has been difficult. Here we show the 2.5 A resolution crystal structure of a region spanning three domains of RyR type 1 (RyR1), encompassing amino acid residues 1-559. The domains interact with each other through a predominantly hydrophilic interface. Docking in RyR1 electron microscopy maps unambiguously places the domains in the cytoplasmic portion of the channel, forming a 240-kDa cytoplasmic vestibule around the four-fold symmetry axis. We pinpoint the exact locations of more than 50 disease-associated mutations in full-length RyR1 and RyR2. The mutations can be classified into three groups: those that destabilize the interfaces between the three amino-terminal domains, disturb the folding of individual domains or affect one of six interfaces with other parts of the receptor. We propose a model whereby the opening of a RyR coincides with allosterically coupled motions within the N-terminal domains. This process can be affected by mutations that target various interfaces within and across subunits. The crystal structure provides a framework to understand the many disease-associated mutations in RyRs that have been studied using functional methods, and will be useful for developing new strategies to modulate RyR function in disease states.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tung, Ching-Chieh -- Lobo, Paolo A -- Kimlicka, Lynn -- Van Petegem, Filip -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2010 Nov 25;468(7323):585-8. doi: 10.1038/nature09471. Epub 2010 Nov 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21048710" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Models, Molecular ; Mutation/genetics ; Protein Structure, Tertiary ; Rabbits ; Ryanodine Receptor Calcium Release Channel/*chemistry/*genetics/metabolism
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  • 22
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    Nature Publishing Group (NPG)
    Publication Date: 2010-11-12
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2010 Nov 11;468(7321):133-4. doi: 10.1038/468133b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21068782" target="_blank"〉PubMed〈/a〉
    Keywords: California ; Canada ; *Climate Change/economics ; Environmental Policy/economics/*legislation & jurisprudence ; *Federal Government ; Leadership ; *State Government ; United States
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  • 23
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    Nature Publishing Group (NPG)
    Publication Date: 2010-06-26
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schiermeier, Quirin -- England -- Nature. 2010 Jun 24;465(7301):996. doi: 10.1038/465996a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20577180" target="_blank"〉PubMed〈/a〉
    Keywords: Budgets ; *Federal Government ; Financing, Government/*economics ; Germany ; Schools, Medical/economics ; Universities/*economics/organization & administration
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  • 24
    Publication Date: 2010-07-14
    Description: While reversible histone modifications are linked to an ever-expanding range of biological functions, the demethylases for histone H4 lysine 20 and their potential regulatory roles remain unknown. Here we report that the PHD and Jumonji C (JmjC) domain-containing protein, PHF8, while using multiple substrates, including H3K9me1/2 and H3K27me2, also functions as an H4K20me1 demethylase. PHF8 is recruited to promoters by its PHD domain based on interaction with H3K4me2/3 and controls G1-S transition in conjunction with E2F1, HCF-1 (also known as HCFC1) and SET1A (also known as SETD1A), at least in part, by removing the repressive H4K20me1 mark from a subset of E2F1-regulated gene promoters. Phosphorylation-dependent PHF8 dismissal from chromatin in prophase is apparently required for the accumulation of H4K20me1 during early mitosis, which might represent a component of the condensin II loading process. Accordingly, the HEAT repeat clusters in two non-structural maintenance of chromosomes (SMC) condensin II subunits, N-CAPD3 and N-CAPG2 (also known as NCAPD3 and NCAPG2, respectively), are capable of recognizing H4K20me1, and ChIP-Seq analysis demonstrates a significant overlap of condensin II and H4K20me1 sites in mitotic HeLa cells. Thus, the identification and characterization of an H4K20me1 demethylase, PHF8, has revealed an intimate link between this enzyme and two distinct events in cell cycle progression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059551/" 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/PMC3059551/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Wen -- Tanasa, Bogdan -- Tyurina, Oksana V -- Zhou, Tian Yuan -- Gassmann, Reto -- Liu, Wei Ting -- Ohgi, Kenneth A -- Benner, Chris -- Garcia-Bassets, Ivan -- Aggarwal, Aneel K -- Desai, Arshad -- Dorrestein, Pieter C -- Glass, Christopher K -- Rosenfeld, Michael G -- R01 CA097134/CA/NCI NIH HHS/ -- R01 CA097134-09/CA/NCI NIH HHS/ -- R01 DK018477/DK/NIDDK NIH HHS/ -- R01 DK018477-35/DK/NIDDK NIH HHS/ -- R01 DK039949/DK/NIDDK NIH HHS/ -- R01 DK039949-18/DK/NIDDK NIH HHS/ -- R01 HL065445/HL/NHLBI NIH HHS/ -- R01 NS034934/NS/NINDS NIH HHS/ -- R01 NS034934-21/NS/NINDS NIH HHS/ -- R37 DK039949/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Jul 22;466(7305):508-12. doi: 10.1038/nature09272. Epub 2010 Jul 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, School of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20622854" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/chemistry/metabolism ; Cell Cycle/*physiology ; Cell Line ; Chromatin/metabolism ; Chromosomal Proteins, Non-Histone/chemistry/deficiency/genetics/*metabolism ; DNA-Binding Proteins/chemistry/metabolism ; HeLa Cells ; Histone Demethylases/chemistry/genetics/*metabolism ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/chemistry/*metabolism ; Host Cell Factor C1/genetics/metabolism ; Humans ; Lysine/*metabolism ; Methylation ; Multiprotein Complexes/chemistry/metabolism ; Phosphorylation ; Promoter Regions, Genetic ; Protein Structure, Tertiary ; Transcription Factors/chemistry/deficiency/genetics/*metabolism
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  • 25
    Publication Date: 2010-07-30
    Description: The post-translational methylation of alpha-amino groups was first discovered over 30 years ago on the bacterial ribosomal proteins L16 and L33 (refs 1, 2), but almost nothing is known about the function or enzymology of this modification. Several other bacterial and eukaryotic proteins have since been shown to be alpha-N-methylated. However, the Ran guanine nucleotide-exchange factor, RCC1, is the only protein for which any biological function of alpha-N-methylation has been identified. Methylation-defective mutants of RCC1 have reduced affinity for DNA and cause mitotic defects, but further characterization of this modification has been hindered by ignorance of the responsible methyltransferase. All fungal and animal N-terminally methylated proteins contain a unique N-terminal motif, Met-(Ala/Pro/Ser)-Pro-Lys, indicating that they may be targets of the same, unknown enzyme. The initiating Met is cleaved, and the exposed alpha-amino group is mono-, di- or trimethylated. Here we report the discovery of the first alpha-N-methyltransferase, which we named N-terminal RCC1 methyltransferase (NRMT). Substrate docking and mutational analysis of RCC1 defined the NRMT recognition sequence and enabled the identification of numerous new methylation targets, including SET (also known as TAF-I or PHAPII) and the retinoblastoma protein, RB. Knockdown of NRMT recapitulates the multi-spindle phenotype seen with methylation-defective RCC1 mutants, demonstrating the importance of alpha-N-methylation for normal bipolar spindle formation and chromosome segregation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939154/" 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/PMC2939154/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tooley, Christine E Schaner -- Petkowski, Janusz J -- Muratore-Schroeder, Tara L -- Balsbaugh, Jeremy L -- Shabanowitz, Jeffrey -- Sabat, Michal -- Minor, Wladek -- Hunt, Donald F -- Macara, Ian G -- R01 GM050526/GM/NIGMS NIH HHS/ -- R01 GM050526-17/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Aug 26;466(7310):1125-8. doi: 10.1038/nature09343.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology, Center for Cell Signaling, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA. ces5g@virginia.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20668449" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Cycle Proteins/*metabolism ; Cell Line ; Chromosome Segregation ; Gene Knockdown Techniques ; Guanine Nucleotide Exchange Factors/*metabolism ; HeLa Cells ; Histone Chaperones/metabolism ; Humans ; Methyltransferases/chemistry/genetics/*metabolism ; Models, Molecular ; Mutation/genetics ; Nuclear Proteins/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Retinoblastoma Protein/*metabolism ; Spindle Apparatus/metabolism ; Transcription Factors/metabolism
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  • 26
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    Nature Publishing Group (NPG)
    Publication Date: 2010-09-03
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lok, Corie -- England -- Nature. 2010 Sep 2;467(7311):18-21. doi: 10.1038/467018a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20811430" target="_blank"〉PubMed〈/a〉
    Keywords: Chemistry ; Financing, Government/legislation & jurisprudence ; Nanostructures/chemistry ; *Nanotechnology/economics ; *Research Support as Topic
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  • 27
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    Nature Publishing Group (NPG)
    Publication Date: 2010-05-14
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2010 May 13;465(7295):135. doi: 10.1038/465135a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20463693" target="_blank"〉PubMed〈/a〉
    Keywords: *Federal Government ; Great Britain ; Politics ; Public Policy ; *Research Personnel/economics ; Science/economics/*legislation & jurisprudence/trends
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  • 28
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    Nature Publishing Group (NPG)
    Publication Date: 2010-09-17
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Macilwain, Colin -- England -- Nature. 2010 Sep 16;467(7313):269. doi: 10.1038/467269a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉cfmworldview@gmail.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20844513" target="_blank"〉PubMed〈/a〉
    Keywords: *Federal Government ; Financing, Government/*economics/statistics & numerical data/trends ; Great Britain ; Research Support as Topic/*economics/statistics & numerical data/trends ; Science/*economics/trends ; Universities/economics
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  • 29
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    Nature Publishing Group (NPG)
    Publication Date: 2010-04-16
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Borrell, Brendan -- England -- Nature. 2010 Apr 15;464(7291):971. doi: 10.1038/464971a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20393533" target="_blank"〉PubMed〈/a〉
    Keywords: Clinical Trials as Topic/ethics ; *Ethicists ; Ethics Committees/*organization & administration ; *Federal Government ; Humans ; Stem Cells ; United States
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  • 30
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    Nature Publishing Group (NPG)
    Publication Date: 2010-04-24
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2010 Apr 22;464(7292):1103-4. doi: 10.1038/4641103b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20414265" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Benzhydryl Compounds ; Chemical Industry/*legislation & jurisprudence/*standards ; *Evaluation Studies as Topic ; *Federal Government ; Guidelines as Topic ; Humans ; Phenols/adverse effects/toxicity ; Reproducibility of Results ; Safety/*legislation & jurisprudence/*standards ; *Toxicity Tests/methods/standards ; United States
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  • 31
    Publication Date: 2010-05-14
    Description: A huge variety of proteins are able to form fibrillar structures, especially at high protein concentrations. Hence, it is surprising that spider silk proteins can be stored in a soluble form at high concentrations and transformed into extremely stable fibres on demand. Silk proteins are reminiscent of amphiphilic block copolymers containing stretches of polyalanine and glycine-rich polar elements forming a repetitive core flanked by highly conserved non-repetitive amino-terminal and carboxy-terminal domains. The N-terminal domain comprises a secretion signal, but further functions remain unassigned. The C-terminal domain was implicated in the control of solubility and fibre formation initiated by changes in ionic composition and mechanical stimuli known to align the repetitive sequence elements and promote beta-sheet formation. However, despite recent structural data, little is known about this remarkable behaviour in molecular detail. Here we present the solution structure of the C-terminal domain of a spider dragline silk protein and provide evidence that the structural state of this domain is essential for controlled switching between the storage and assembly forms of silk proteins. In addition, the C-terminal domain also has a role in the alignment of secondary structural features formed by the repetitive elements in the backbone of spider silk proteins, which is known to be important for the mechanical properties of the fibre.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hagn, Franz -- Eisoldt, Lukas -- Hardy, John G -- Vendrely, Charlotte -- Coles, Murray -- Scheibel, Thomas -- Kessler, Horst -- England -- Nature. 2010 May 13;465(7295):239-42. doi: 10.1038/nature08936.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Integrated Protein Science (CIPSM), Technische Universitat Munchen, 85747 Garching, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20463741" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calorimetry, Differential Scanning ; Circular Dichroism ; *Conserved Sequence ; Hydrophobic and Hydrophilic Interactions ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Protein Structure, Tertiary ; Silk/*chemistry/*metabolism ; Spectrometry, Fluorescence ; Spectroscopy, Fourier Transform Infrared ; Spiders/*chemistry
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  • 32
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    Nature Publishing Group (NPG)
    Publication Date: 2010-10-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kool, Richard -- England -- Nature. 2010 Oct 14;467(7317):788. doi: 10.1038/467788d.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20944722" target="_blank"〉PubMed〈/a〉
    Keywords: *Climate Change ; Conservation of Natural Resources/legislation & jurisprudence ; Environmental Policy/legislation & jurisprudence ; *Federal Government ; *Politics ; *Science ; United States
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  • 33
    Publication Date: 2010-09-28
    Description: Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein-protein interactions of epigenetic 'readers', and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010259/" 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/PMC3010259/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Filippakopoulos, Panagis -- Qi, Jun -- Picaud, Sarah -- Shen, Yao -- Smith, William B -- Fedorov, Oleg -- Morse, Elizabeth M -- Keates, Tracey -- Hickman, Tyler T -- Felletar, Ildiko -- Philpott, Martin -- Munro, Shonagh -- McKeown, Michael R -- Wang, Yuchuan -- Christie, Amanda L -- West, Nathan -- Cameron, Michael J -- Schwartz, Brian -- Heightman, Tom D -- La Thangue, Nicholas -- French, Christopher A -- Wiest, Olaf -- Kung, Andrew L -- Knapp, Stefan -- Bradner, James E -- 13058/Cancer Research UK/United Kingdom -- G0500905/Medical Research Council/United Kingdom -- G1000807/Medical Research Council/United Kingdom -- G9400953/Medical Research Council/United Kingdom -- K08 CA128972/CA/NCI NIH HHS/ -- K08 CA128972-03/CA/NCI NIH HHS/ -- T32-075762/PHS HHS/ -- Canadian Institutes of Health Research/Canada -- Wellcome Trust/United Kingdom -- England -- Nature. 2010 Dec 23;468(7327):1067-73. doi: 10.1038/nature09504. Epub 2010 Sep 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20871596" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Azirines/chemical synthesis/chemistry/*pharmacology ; Binding Sites ; Carcinoma, Squamous Cell/physiopathology ; Cell Differentiation/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Chromatin/metabolism ; Dihydropyridines/chemical synthesis/chemistry/*pharmacology ; Female ; Humans ; Mice ; Mice, Nude ; *Models, Molecular ; Molecular Sequence Data ; Nuclear Proteins/*antagonists & inhibitors/*metabolism ; Protein Binding/drug effects ; Protein Structure, Tertiary ; Recombinant Proteins/metabolism ; Sequence Alignment ; Skin Neoplasms/physiopathology ; Stereoisomerism ; Transcription Factors/*antagonists & inhibitors/*metabolism
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  • 34
    Publication Date: 2010-06-19
    Description: Transcription of eukaryotic messenger RNA (mRNA) encoding genes by RNA polymerase II (Pol II) is triggered by the binding of transactivating proteins to enhancer DNA, which stimulates the recruitment of general transcription factors (TFIIA, B, D, E, F, H) and Pol II on the cis-linked promoter, leading to pre-initiation complex formation and transcription. In TFIID-dependent activation pathways, this general transcription factor containing TATA-box-binding protein is first recruited on the promoter through interaction with activators and cooperates with TFIIA to form a committed pre-initiation complex. However, neither the mechanisms by which activation signals are communicated between these factors nor the structural organization of the activated pre-initiation complex are known. Here we used cryo-electron microscopy to determine the architecture of nucleoprotein complexes composed of TFIID, TFIIA, the transcriptional activator Rap1 and yeast enhancer-promoter DNA. These structures revealed the mode of binding of Rap1 and TFIIA to TFIID, as well as a reorganization of TFIIA induced by its interaction with Rap1. We propose that this change in position increases the exposure of TATA-box-binding protein within TFIID, consequently enhancing its ability to interact with the promoter. A large Rap1-dependent DNA loop forms between the activator-binding site and the proximal promoter region. This loop is topologically locked by a TFIIA-Rap1 protein bridge that folds over the DNA. These results highlight the role of TFIIA in transcriptional activation, define a molecular mechanism for enhancer-promoter communication and provide structural insights into the pathways of intramolecular communication that convey transcription activation signals through the TFIID complex.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2900199/" 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/PMC2900199/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Papai, Gabor -- Tripathi, Manish K -- Ruhlmann, Christine -- Layer, Justin H -- Weil, P Anthony -- Schultz, Patrick -- GM52461/GM/NIGMS NIH HHS/ -- R01 GM052461/GM/NIGMS NIH HHS/ -- R01 GM052461-14/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Jun 17;465(7300):956-60. doi: 10.1038/nature09080.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Structural Biology and Genomics, Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), 1 rue Laurent Fries, BP10142, 67404 Illkirch, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20559389" target="_blank"〉PubMed〈/a〉
    Keywords: Cryoelectron Microscopy ; *Models, Molecular ; Nucleoproteins/chemistry/ultrastructure ; Protein Structure, Tertiary ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism/ultrastructure ; Telomere-Binding Proteins/chemistry/*metabolism/ultrastructure ; Transcription Factor TFIIA/chemistry/*metabolism ; Transcription Factor TFIID/chemistry/*metabolism ; Transcription Factors/chemistry/*metabolism/ultrastructure ; *Transcriptional Activation
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  • 35
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    Nature Publishing Group (NPG)
    Publication Date: 2010-10-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2010 Oct 14;467(7317):751. doi: 10.1038/467751a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20944684" target="_blank"〉PubMed〈/a〉
    Keywords: American Recovery and Reinvestment Act ; Comparative Effectiveness Research/legislation & jurisprudence ; Electronic Health Records/legislation & jurisprudence ; Embryonic Stem Cells ; *Federal Government ; Greenhouse Effect/legislation & jurisprudence/prevention & control ; Humans ; *Politics ; Stem Cell Research/legislation & jurisprudence ; United States
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  • 36
    Publication Date: 2010-12-18
    Description: Recognition of modified histone species by distinct structural domains within 'reader' proteins plays a critical role in the regulation of gene expression. Readers that simultaneously recognize histones with multiple marks allow transduction of complex chromatin modification patterns into specific biological outcomes. Here we report that chromatin regulator tripartite motif-containing 24 (TRIM24) functions in humans as a reader of dual histone marks by means of tandem plant homeodomain (PHD) and bromodomain (Bromo) regions. The three-dimensional structure of the PHD-Bromo region of TRIM24 revealed a single functional unit for combinatorial recognition of unmodified H3K4 (that is, histone H3 unmodified at lysine 4, H3K4me0) and acetylated H3K23 (histone H3 acetylated at lysine 23, H3K23ac) within the same histone tail. TRIM24 binds chromatin and oestrogen receptor to activate oestrogen-dependent genes associated with cellular proliferation and tumour development. Aberrant expression of TRIM24 negatively correlates with survival of breast cancer patients. The PHD-Bromo of TRIM24 provides a structural rationale for chromatin activation through a non-canonical histone signature, establishing a new route by which chromatin readers may influence cancer pathogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058826/" 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/PMC3058826/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tsai, Wen-Wei -- Wang, Zhanxin -- Yiu, Teresa T -- Akdemir, Kadir C -- Xia, Weiya -- Winter, Stefan -- Tsai, Cheng-Yu -- Shi, Xiaobing -- Schwarzer, Dirk -- Plunkett, William -- Aronow, Bruce -- Gozani, Or -- Fischle, Wolfgang -- Hung, Mien-Chie -- Patel, Dinshaw J -- Barton, Michelle Craig -- GM079641/GM/NIGMS NIH HHS/ -- GM081627/GM/NIGMS NIH HHS/ -- P01 GM081627/GM/NIGMS NIH HHS/ -- P01 GM081627-010003/GM/NIGMS NIH HHS/ -- P01 GM081627-020003/GM/NIGMS NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- P30DK078392-01/DK/NIDDK NIH HHS/ -- T32 HD07325/HD/NICHD NIH HHS/ -- U54 RR025216/RR/NCRR NIH HHS/ -- UL1 TR000077/TR/NCATS NIH HHS/ -- England -- Nature. 2010 Dec 16;468(7326):927-32. doi: 10.1038/nature09542.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, Program in Genes and Development, Graduate School of Biomedical Sciences, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21164480" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Breast Neoplasms/*genetics/*metabolism/pathology ; Carrier Proteins/chemistry/genetics/*metabolism ; Cell Line, Tumor ; Chromatin/metabolism ; Chromatin Assembly and Disassembly ; Crystallography, X-Ray ; Estrogen Receptor alpha/metabolism ; Estrogens/metabolism ; *Gene Expression Regulation, Neoplastic/genetics ; HEK293 Cells ; Histones/chemistry/*metabolism ; Humans ; Methylation ; Protein Array Analysis ; Protein Binding ; Protein Structure, Tertiary ; Substrate Specificity ; Survival Rate
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  • 37
    Publication Date: 2010-01-08
    Description: Eukaryotic DNA replication uses kinase regulatory pathways to facilitate coordination with other processes during cell division cycles and response to environmental cues. At least two cell cycle-regulated protein kinase systems, the S-phase-specific cyclin-dependent protein kinases (S-CDKs) and the Dbf4-Cdc7 kinase (DDK, Dbf4-dependent protein kinase) are essential activators for initiation of DNA replication. Although the essential mechanism of CDK activation of DNA replication in Saccharomyces cerevisiae has been established, exactly how DDK acts has been unclear. Here we show that the amino terminal serine/threonine-rich domain (NSD) of Mcm4 has both inhibitory and facilitating roles in DNA replication control and that the sole essential function of DDK is to relieve an inhibitory activity residing within the NSD. By combining an mcm4 mutant lacking the inhibitory activity with mutations that bypass the requirement for CDKs for initiation of DNA replication, we show that DNA synthesis can occur in G1 phase when CDKs and DDK are limited. However, DDK is still required for efficient S phase progression. In the absence of DDK, CDK phosphorylation at the distal part of the Mcm4 NSD becomes crucial. Moreover, DDK-null cells fail to activate the intra-S-phase checkpoint in the presence of hydroxyurea-induced DNA damage and are unable to survive this challenge. Our studies establish that the eukaryote-specific NSD of Mcm4 has evolved to integrate several protein kinase regulatory signals for progression through S phase.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2805463/" 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/PMC2805463/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sheu, Yi-Jun -- Stillman, Bruce -- R01 GM045436/GM/NIGMS NIH HHS/ -- R01 GM045436-18/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Jan 7;463(7277):113-7. doi: 10.1038/nature08647.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20054399" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Cycle Proteins/antagonists & inhibitors/chemistry/genetics/*metabolism ; Cell Proliferation/drug effects ; DNA Damage ; DNA-Binding Proteins/antagonists & inhibitors/chemistry/genetics/*metabolism ; G1 Phase/drug effects ; Genes, Essential ; Hydroxyurea/pharmacology ; Microbial Viability/drug effects ; Minichromosome Maintenance Complex Component 4 ; Phosphorylation ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/deficiency/genetics/*metabolism ; S Phase/drug effects/*physiology ; Saccharomyces cerevisiae/*cytology/enzymology/growth & development/*metabolism ; Saccharomyces cerevisiae Proteins/antagonists & ; inhibitors/chemistry/genetics/*metabolism ; Sequence Deletion ; Substrate Specificity
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  • 38
    Publication Date: 2010-10-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wadman, Meredith -- England -- Nature. 2010 Oct 14;467(7317):761. doi: 10.1038/467761a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20944702" target="_blank"〉PubMed〈/a〉
    Keywords: Budgets ; *Federal Government ; Humans ; National Institutes of Health (U.S.)/economics/*legislation & jurisprudence ; *Politics ; Research Support as Topic/economics/trends ; Stem Cell Research/economics/*legislation & jurisprudence ; United States
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  • 39
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    Nature Publishing Group (NPG)
    Publication Date: 2010-06-26
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mascarelli, Amanda -- England -- Nature. 2010 Jun 24;465(7301):993. doi: 10.1038/465993b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20577177" target="_blank"〉PubMed〈/a〉
    Keywords: *Disasters ; *Ecosystem ; *Federal Government ; Industry/*economics/*legislation & jurisprudence ; Mexico ; Oceans and Seas ; Petroleum/*adverse effects ; Research/*economics ; Seawater/*chemistry ; United States
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  • 40
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    Publication Date: 2010-10-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Greenberg, Daniel S -- England -- Nature. 2010 Oct 14;467(7317):781-2. doi: 10.1038/467781a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉danielg523@aol.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20944714" target="_blank"〉PubMed〈/a〉
    Keywords: Age Factors ; Budgets/trends ; Conflict of Interest/legislation & jurisprudence ; *Federal Government ; Humans ; Military Science/economics/legislation & jurisprudence ; National Institutes of Health (U.S.)/economics ; Policy Making ; Research Support as Topic/*legislation & jurisprudence/*trends ; Science/economics/*legislation & jurisprudence/*trends ; United States
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  • 41
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    Nature Publishing Group (NPG)
    Publication Date: 2010-08-06
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2010 Aug 5;466(7307):667. doi: 10.1038/466667b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20686526" target="_blank"〉PubMed〈/a〉
    Keywords: *Federal Government ; Global Warming/*legislation & jurisprudence/*prevention & control ; *Politics ; United States
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  • 42
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    Nature Publishing Group (NPG)
    Publication Date: 2008-05-08
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wadman, Meredith -- England -- Nature. 2008 May 1;453(7191):9. doi: 10.1038/453009a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18461710" target="_blank"〉PubMed〈/a〉
    Keywords: *Federal Government ; Genetic Privacy/*legislation & jurisprudence ; Genetics, Medical/*legislation & jurisprudence ; Genomics/legislation & jurisprudence/trends ; Humans ; Individuality ; *Prejudice ; United States
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  • 43
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    Nature Publishing Group (NPG)
    Publication Date: 2008-12-05
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2008 Dec 4;456(7222):545. doi: 10.1038/456545a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19052574" target="_blank"〉PubMed〈/a〉
    Keywords: Acquired Immunodeficiency Syndrome/drug therapy/*epidemiology/*mortality ; Anti-HIV Agents/*supply & distribution ; Child ; *Federal Government ; Female ; Humans ; Politics ; Pregnancy ; *Public Policy ; South Africa/epidemiology
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  • 44
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    Nature Publishing Group (NPG)
    Publication Date: 2008-09-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gault, Fred -- Huttner, Susanne -- England -- Nature. 2008 Sep 25;455(7212):462-3. doi: 10.1038/455462a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉OECD Innovation Strategy, Paris, France. fgault@idrc.ca〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18818635" target="_blank"〉PubMed〈/a〉
    Keywords: *Federal Government ; Greenhouse Effect ; Guidelines as Topic ; *Internationality ; Technology/economics/*organization & administration/trends
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  • 45
    Publication Date: 2008-10-31
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Siddiqi, Muhammad Naim -- Yusufzai, Abdul Wahab -- England -- Nature. 2008 Oct 30;455(7217):1175-6. doi: 10.1038/4551175c.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18971997" target="_blank"〉PubMed〈/a〉
    Keywords: Budgets ; *Federal Government ; *Military Personnel ; Pakistan ; *Science/economics
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    Nature Publishing Group (NPG)
    Publication Date: 2008-11-21
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2008 Nov 20;456(7220):282. doi: 10.1038/456282a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19020565" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line ; *Federal Government ; Humans ; Leadership ; National Institutes of Health (U.S.)/*organization & administration ; *Stem Cells/cytology ; United States
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    Nature Publishing Group (NPG)
    Publication Date: 2008-10-31
    Description: The values of scientific enquiry, rather than any particular policy positions on science, suggest a preference for one US presidential candidate over the other.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2008 Oct 30;455(7217):1149. doi: 10.1038/4551149a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18971969" target="_blank"〉PubMed〈/a〉
    Keywords: *Federal Government ; *Politics ; *Science/standards ; United States
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  • 48
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    Nature Publishing Group (NPG)
    Publication Date: 2008-02-22
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Smaglik, Paul -- England -- Nature. 2008 Jan 24;451(7177):494-6. doi: 10.1038/nj7177-494a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18290265" target="_blank"〉PubMed〈/a〉
    Keywords: Argentina ; Emigration and Immigration/history/trends ; *Federal Government ; History, 20th Century ; History, 21st Century ; Politics ; Research Personnel/economics/history/*trends ; Research Support as Topic/economics/history ; Salaries and Fringe Benefits ; Science/*economics/history/manpower/*organization & administration
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  • 49
    Publication Date: 2008-01-04
    Description: Synthesis of proteins containing errors (mistranslation) is prevented by aminoacyl transfer RNA synthetases through their accurate aminoacylation of cognate tRNAs and their ability to correct occasional errors of aminoacylation by editing reactions. A principal source of mistranslation comes from mistaking glycine or serine for alanine, which can lead to serious cell and animal pathologies, including neurodegeneration. A single specific G.U base pair (G3.U70) marks a tRNA for aminoacylation by alanyl-tRNA synthetase. Mistranslation occurs when glycine or serine is joined to the G3.U70-containing tRNAs, and is prevented by the editing activity that clears the mischarged amino acid. Previously it was assumed that the specificity for recognition of tRNA(Ala) for editing was provided by the same structural determinants as used for aminoacylation. Here we show that the editing site of alanyl-tRNA synthetase, as an artificial recombinant fragment, targets mischarged tRNA(Ala) using a structural motif unrelated to that for aminoacylation so that, remarkably, two motifs (one for aminoacylation and one for editing) in the same enzyme independently can provide determinants for tRNA(Ala) recognition. The structural motif for editing is also found naturally in genome-encoded protein fragments that are widely distributed in evolution. These also recognize mischarged tRNA(Ala). Thus, through evolution, three different complexes with the same tRNA can guard against mistaking glycine or serine for alanine.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Beebe, Kirk -- Mock, Marissa -- Merriman, Eve -- Schimmel, Paul -- England -- Nature. 2008 Jan 3;451(7174):90-3. doi: 10.1038/nature06454.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology and Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18172502" target="_blank"〉PubMed〈/a〉
    Keywords: Alanine-tRNA Ligase/*chemistry/*metabolism ; Amino Acid Motifs ; *Base Pairing ; Binding Sites ; Escherichia coli/enzymology ; Peptide Fragments/chemistry/metabolism ; Protein Biosynthesis ; Protein Structure, Tertiary ; RNA, Transfer, Ala/*chemistry/genetics/*metabolism ; Substrate Specificity
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  • 50
    Publication Date: 2008-08-30
    Description: The slicer activity of the RNA-induced silencing complex is associated with argonaute, the RNase H-like PIWI domain of which catalyses guide-strand-mediated sequence-specific cleavage of target messenger RNA. Here we report on the crystal structure of Thermus thermophilus argonaute bound to a 5'-phosphorylated 21-base DNA guide strand, thereby identifying the nucleic-acid-binding channel positioned between the PAZ- and PIWI-containing lobes, as well as the pivot-like conformational changes associated with complex formation. The bound guide strand is anchored at both of its ends, with the solvent-exposed Watson-Crick edges of stacked bases 2 to 6 positioned for nucleation with the mRNA target, whereas two critically positioned arginines lock bases 10 and 11 at the cleavage site into an unanticipated orthogonal alignment. Biochemical studies indicate that key amino acid residues at the active site and those lining the 5'-phosphate-binding pocket made up of the Mid domain are critical for cleavage activity, whereas alterations of residues lining the 2-nucleotide 3'-end-binding pocket made up of the PAZ domain show little effect.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689319/" 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/PMC4689319/" 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 -- Sheng, Gang -- Juranek, Stefan -- Tuschl, Thomas -- Patel, Dinshaw J -- P30 CA008748/CA/NCI NIH HHS/ -- R01 AI068776/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Nov 13;456(7219):209-13. doi: 10.1038/nature07315. Epub 2008 Aug 27.〈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/18754009" target="_blank"〉PubMed〈/a〉
    Keywords: Aptamers, Nucleotide/metabolism ; Bacterial Proteins/*chemistry/metabolism ; Crystallography, X-Ray ; *Gene Silencing ; Hydrogen Bonding ; *Models, Molecular ; Mutation ; Protein Structure, Tertiary ; RNA/metabolism ; Thermus thermophilus/*chemistry/genetics
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    Nature Publishing Group (NPG)
    Publication Date: 2008-10-17
    Description: In an attempt to boost its struggling economy, Italy's government is focusing on easy, but unwise, targets.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2008 Oct 16;455(7215):835-6. doi: 10.1038/455835b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18923461" target="_blank"〉PubMed〈/a〉
    Keywords: Budgets ; Employment/economics ; *Federal Government ; Italy ; Research Personnel/*economics ; Research Support as Topic/*economics ; Universities/economics
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  • 52
    Publication Date: 2008-09-02
    Description: A common hallmark of human cancers is the overexpression of telomerase, a ribonucleoprotein complex that is responsible for maintaining the length and integrity of chromosome ends. Telomere length deregulation and telomerase activation is an early, and perhaps necessary, step in cancer cell evolution. Here we present the high-resolution structure of the Tribolium castaneum catalytic subunit of telomerase, TERT. The protein consists of three highly conserved domains, organized into a ring-like structure that shares common features with retroviral reverse transcriptases, viral RNA polymerases and B-family DNA polymerases. Domain organization places motifs implicated in substrate binding and catalysis in the interior of the ring, which can accommodate seven to eight bases of double-stranded nucleic acid. Modelling of an RNA-DNA heteroduplex in the interior of this ring demonstrates a perfect fit between the protein and the nucleic acid substrate, and positions the 3'-end of the DNA primer at the active site of the enzyme, providing evidence for the formation of an active telomerase elongation complex.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gillis, Andrew J -- Schuller, Anthony P -- Skordalakes, Emmanuel -- England -- Nature. 2008 Oct 2;455(7213):633-7. doi: 10.1038/nature07283. Epub 2008 Aug 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gene Expression and Regulation Program, The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18758444" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Animals ; Binding Sites ; Catalysis ; Catalytic Domain ; Conserved Sequence ; Crystallization ; Crystallography, X-Ray ; Humans ; Models, Molecular ; Nucleotides/metabolism ; Protein Structure, Tertiary ; Telomerase/*chemistry/metabolism ; Tribolium/*enzymology
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    Nature Publishing Group (NPG)
    Publication Date: 2008-12-05
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wassarman, Paul M -- England -- Nature. 2008 Dec 4;456(7222):586-7. doi: 10.1038/456586a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19052615" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Conserved Sequence ; Crystallography, X-Ray ; Egg Proteins/*chemistry/genetics/*metabolism ; Female ; Fertilization/physiology ; Male ; Membrane Glycoproteins/*chemistry/genetics/*metabolism ; Mice ; Ovum/*chemistry/*metabolism ; Protein Folding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Receptors, Cell Surface/*chemistry/genetics/*metabolism ; Spermatozoa/metabolism
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    Publication Date: 2008-03-28
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Prentice, Jim -- England -- Nature. 2008 Mar 27;452(7186):409. doi: 10.1038/452409a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18368098" target="_blank"〉PubMed〈/a〉
    Keywords: Canada ; *Federal Government ; Science/*economics/*standards
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    Publication Date: 2008-10-04
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2008 Oct 2;455(7213):565. doi: 10.1038/455565a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18833221" target="_blank"〉PubMed〈/a〉
    Keywords: Conservation of Energy Resources/economics/*trends ; Economics/*trends ; *Federal Government ; Greenhouse Effect ; Technology/economics/*trends ; United States
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    Nature Publishing Group (NPG)
    Publication Date: 2008-11-07
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goldston, David -- England -- Nature. 2008 Nov 6;456(7218):16. doi: 10.1038/456016a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18987708" target="_blank"〉PubMed〈/a〉
    Keywords: Conservation of Energy Resources/economics/legislation & jurisprudence/trends ; *Federal Government ; Humans ; Leadership ; National Institutes of Health (U.S.)/economics ; Research Personnel/economics/psychology ; Research Support as Topic/*economics/legislation & jurisprudence/trends ; Science/*economics/legislation & jurisprudence/trends ; United States ; United States National Aeronautics and Space Administration/economics
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    Publication Date: 2008-09-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2008 Sep 25;455(7212):431. doi: 10.1038/455431a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18818598" target="_blank"〉PubMed〈/a〉
    Keywords: Embryonic Stem Cells ; *Federal Government ; Greenhouse Effect ; Humans ; *Politics ; Religion and Science ; Research Support as Topic ; Science/*economics/trends ; United States
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    Nature Publishing Group (NPG)
    Publication Date: 2008-09-19
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2008 Sep 18;455(7211):273. doi: 10.1038/455273b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18800096" target="_blank"〉PubMed〈/a〉
    Keywords: Competitive Behavior ; *Creativity ; *Federal Government ; Leadership ; United States
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  • 59
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    Publication Date: 2008-09-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goldston, David -- England -- Nature. 2008 Sep 25;455(7212):453. doi: 10.1038/455453a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18818626" target="_blank"〉PubMed〈/a〉
    Keywords: Confidentiality ; *Federal Government ; Science/*organization & administration/trends ; United States
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    Publication Date: 2008-09-05
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goldston, David -- England -- Nature. 2008 Sep 4;455(7209):15. doi: 10.1038/455015a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉House Committee on Science. partyofone@gmail.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18769410" target="_blank"〉PubMed〈/a〉
    Keywords: Ecosystem ; *Environmental Monitoring/economics ; *Federal Government ; *Politics ; United States
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    Publication Date: 2008-08-08
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goldston, David -- England -- Nature. 2008 Aug 7;454(7205):680. doi: 10.1038/454680a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉House Committee on Science. partyofonecolumn@gmail.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18685673" target="_blank"〉PubMed〈/a〉
    Keywords: Budgets/*legislation & jurisprudence/*trends ; *Federal Government ; *Politics ; Research Support as Topic/economics/*legislation & jurisprudence ; Science/*economics/legislation & jurisprudence ; Time Factors ; United States
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    Publication Date: 2008-09-19
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2008 Sep 18;455(7211):263. doi: 10.1038/455263a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18800079" target="_blank"〉PubMed〈/a〉
    Keywords: Canada ; *Federal Government ; Greenhouse Effect ; Politics ; Research Personnel ; Science/*trends
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 63
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    Publication Date: 2008-07-04
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goldston, David -- England -- Nature. 2008 Jul 3;454(7200):16. doi: 10.1038/454016a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Harvard University's Center for the Environment, USA. partyofonecolumn@gmail.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18596778" target="_blank"〉PubMed〈/a〉
    Keywords: Conservation of Natural Resources/economics/legislation & jurisprudence ; *Federal Government ; Hydrogen-Ion Concentration ; *Lobbying ; Oceans and Seas ; Policy Making ; Seawater/*chemistry ; United States
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  • 64
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    Nature Publishing Group (NPG)
    Publication Date: 2008-06-13
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goldston, David -- England -- Nature. 2008 Jun 12;453(7197):838. doi: 10.1038/453838a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Harvard University's Center for the Environment, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18548041" target="_blank"〉PubMed〈/a〉
    Keywords: Biomedical Research/*economics ; *Federal Government ; Humans ; National Institutes of Health (U.S.)/*economics ; Technology Transfer ; United States
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  • 65
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    Nature Publishing Group (NPG)
    Publication Date: 2008-04-04
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goldston, David -- England -- Nature. 2008 Apr 3;452(7187):519. doi: 10.1038/452519a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Harvard University's Center for the Environment. partyofonecolumn@gmail.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18385707" target="_blank"〉PubMed〈/a〉
    Keywords: Air Pollution/analysis/*legislation & jurisprudence/prevention & control ; *Federal Government ; Humans ; Ozone/analysis/toxicity ; Plants/drug effects ; Smog/analysis/prevention & control ; Time Factors ; Uncertainty ; United States ; United States Environmental Protection Agency/*legislation & jurisprudence
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  • 66
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    Nature Publishing Group (NPG)
    Publication Date: 2008-02-08
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goldston, David -- England -- Nature. 2008 Feb 7;451(7179):621. doi: 10.1038/451621a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18256639" target="_blank"〉PubMed〈/a〉
    Keywords: Budgets/trends ; *Federal Government ; National Institutes of Health (U.S.)/economics ; *Persuasive Communication ; *Politics ; *Science/economics ; United States
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  • 67
    Publication Date: 2008-09-06
    Description: Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas (TCGA) pilot project aims to assess the value of large-scale multi-dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas--the most common type of adult brain cancer--and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol-3-OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2671642/" 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/PMC2671642/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cancer Genome Atlas Research Network -- R01 CA099041/CA/NCI NIH HHS/ -- R01 CA099041-05/CA/NCI NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- U24 CA126543-01/CA/NCI NIH HHS/ -- U24 CA126544/CA/NCI NIH HHS/ -- U24 CA126544-01/CA/NCI NIH HHS/ -- U24 CA126546/CA/NCI NIH HHS/ -- U24 CA126546-01/CA/NCI NIH HHS/ -- U24 CA126551-01/CA/NCI NIH HHS/ -- U24 CA126554/CA/NCI NIH HHS/ -- U24 CA126554-01/CA/NCI NIH HHS/ -- U24 CA126561/CA/NCI NIH HHS/ -- U24 CA126561-01/CA/NCI NIH HHS/ -- U24 CA126563/CA/NCI NIH HHS/ -- U24 CA126563-01/CA/NCI NIH HHS/ -- U24CA126543/CA/NCI NIH HHS/ -- U24CA126544/CA/NCI NIH HHS/ -- U24CA126546/CA/NCI NIH HHS/ -- U24CA126551/CA/NCI NIH HHS/ -- U24CA126554/CA/NCI NIH HHS/ -- U24CA126561/CA/NCI NIH HHS/ -- U24CA126563/CA/NCI NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- U54 HG003067-01/HG/NHGRI NIH HHS/ -- U54 HG003079/HG/NHGRI NIH HHS/ -- U54 HG003079-05/HG/NHGRI NIH HHS/ -- U54 HG003273/HG/NHGRI NIH HHS/ -- U54 HG003273-01/HG/NHGRI NIH HHS/ -- U54HG003067/HG/NHGRI NIH HHS/ -- U54HG003079/HG/NHGRI NIH HHS/ -- U54HG003273/HG/NHGRI NIH HHS/ -- England -- Nature. 2008 Oct 23;455(7216):1061-8. doi: 10.1038/nature07385. Epub 2008 Sep 4.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18772890" target="_blank"〉PubMed〈/a〉
    Keywords: Adolescent ; Adult ; Aged ; Aged, 80 and over ; Brain Neoplasms/*genetics ; DNA Methylation ; DNA Modification Methylases/genetics ; DNA Repair/genetics ; DNA Repair Enzymes/genetics ; Female ; Gene Dosage ; *Gene Expression Regulation, Neoplastic ; Genes, Tumor Suppressor ; Genes, erbB-1/genetics ; Genome, Human/genetics ; *Genomics ; Glioblastoma/*genetics ; Humans ; Male ; Middle Aged ; Models, Molecular ; Mutation/genetics ; Neurofibromin 1/genetics ; Phosphatidylinositol 3-Kinases/genetics ; Protein Structure, Tertiary ; Retrospective Studies ; Signal Transduction/genetics ; Tumor Suppressor Proteins/genetics
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  • 68
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    Nature Publishing Group (NPG)
    Publication Date: 2008-01-25
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goldston, David -- England -- Nature. 2008 Jan 24;451(7177):387. doi: 10.1038/451387a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18216824" target="_blank"〉PubMed〈/a〉
    Keywords: *Budgets/trends ; *Federal Government ; Lobbying ; Politics ; Research/*economics ; Research Support as Topic/*economics ; United States
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  • 69
    Publication Date: 2008-02-29
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wheeler, Philip -- England -- Nature. 2008 Feb 28;451(7182):1050. doi: 10.1038/4511050c.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18305521" target="_blank"〉PubMed〈/a〉
    Keywords: *Conservation of Natural Resources/economics ; Ecology/economics/*manpower ; *Federal Government ; *Research Personnel/economics/standards
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  • 70
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    Nature Publishing Group (NPG)
    Publication Date: 2008-08-30
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2008 Aug 28;454(7208):1030. doi: 10.1038/4541030a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18756204" target="_blank"〉PubMed〈/a〉
    Keywords: *Federal Government ; Pakistan ; Political Systems ; Science/economics/organization & administration/*trends
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  • 71
    Publication Date: 2008-07-04
    Description: Neurotrophins (NTs) are important regulators for the survival, differentiation and maintenance of different peripheral and central neurons. NTs bind to two distinct classes of glycosylated receptor: the p75 neurotrophin receptor (p75(NTR)) and tyrosine kinase receptors (Trks). Whereas p75(NTR) binds to all NTs, the Trk subtypes are specific for each NT. The question of whether NTs stimulate p75(NTR) by inducing receptor homodimerization is still under debate. Here we report the 2.6-A resolution crystal structure of neurotrophin-3 (NT-3) complexed to the ectodomain of glycosylated p75(NTR). In contrast to the previously reported asymmetric complex structure, which contains a dimer of nerve growth factor (NGF) bound to a single ectodomain of deglycosylated p75(NTR) (ref. 3), we show that NT-3 forms a central homodimer around which two glycosylated p75(NTR) molecules bind symmetrically. Symmetrical binding occurs along the NT-3 interfaces, resulting in a 2:2 ligand-receptor cluster. A comparison of the symmetrical and asymmetric structures reveals significant differences in ligand-receptor interactions and p75(NTR) conformations. Biochemical experiments indicate that both NT-3 and NGF bind to p75(NTR) with 2:2 stoichiometry in solution, whereas the 2:1 complexes are the result of artificial deglycosylation. We therefore propose that the symmetrical 2:2 complex reflects a native state of p75(NTR) activation at the cell surface. These results provide a model for NTs-p75(NTR) recognition and signal generation, as well as insights into coordination between p75(NTR) and Trks.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gong, Yong -- Cao, Peng -- Yu, Hong-jun -- Jiang, Tao -- England -- Nature. 2008 Aug 7;454(7205):789-93. doi: 10.1038/nature07089. Epub 2008 Jul 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18596692" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Crystallography, X-Ray ; Dimerization ; Glycosylation ; Humans ; Ligands ; Models, Molecular ; Neurotrophin 3/*chemistry/genetics/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Rats ; Receptor, Nerve Growth Factor/*chemistry/genetics/*metabolism ; Spodoptera
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  • 72
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    Publication Date: 2008-08-30
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2008 Aug 28;454(7208):1029. doi: 10.1038/4541029a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18756202" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Conservation of Natural Resources/*legislation & jurisprudence/trends ; Ecology/*legislation & jurisprudence/methods ; Ecosystem ; *Federal Government ; United States ; United States Government Agencies/legislation & jurisprudence
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  • 73
    Publication Date: 2008-02-26
    Description: The psychosis associated with schizophrenia is characterized by alterations in sensory processing and perception. Some antipsychotic drugs were identified by their high affinity for serotonin 5-HT2A receptors (2AR). Drugs that interact with metabotropic glutamate receptors (mGluR) also have potential for the treatment of schizophrenia. The effects of hallucinogenic drugs, such as psilocybin and lysergic acid diethylamide, require the 2AR and resemble some of the core symptoms of schizophrenia. Here we show that the mGluR2 interacts through specific transmembrane helix domains with the 2AR, a member of an unrelated G-protein-coupled receptor family, to form functional complexes in brain cortex. The 2AR-mGluR2 complex triggers unique cellular responses when targeted by hallucinogenic drugs, and activation of mGluR2 abolishes hallucinogen-specific signalling and behavioural responses. In post-mortem human brain from untreated schizophrenic subjects, the 2AR is upregulated and the mGluR2 is downregulated, a pattern that could predispose to psychosis. These regulatory changes indicate that the 2AR-mGluR2 complex may be involved in the altered cortical processes of schizophrenia, and this complex is therefore a promising new target for the treatment of psychosis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743172/" 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/PMC2743172/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gonzalez-Maeso, Javier -- Ang, Rosalind L -- Yuen, Tony -- Chan, Pokman -- Weisstaub, Noelia V -- Lopez-Gimenez, Juan F -- Zhou, Mingming -- Okawa, Yuuya -- Callado, Luis F -- Milligan, Graeme -- Gingrich, Jay A -- Filizola, Marta -- Meana, J Javier -- Sealfon, Stuart C -- G9811527/Medical Research Council/United Kingdom -- P01 DA012923/DA/NIDA NIH HHS/ -- P01 DA012923-06A10004/DA/NIDA NIH HHS/ -- T32 DA007135/DA/NIDA NIH HHS/ -- T32 DA007135-25S1/DA/NIDA NIH HHS/ -- T32 GM062754/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Mar 6;452(7183):93-7. doi: 10.1038/nature06612. Epub 2008 Feb 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA. javier.maeso@mssm.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18297054" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain/cytology/metabolism ; Cell Line ; Cells, Cultured ; Down-Regulation ; Hallucinogens/metabolism/pharmacology ; Humans ; Mice ; Models, Molecular ; Multiprotein Complexes/chemistry/genetics/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Psychotic Disorders/drug therapy/genetics/*metabolism ; Receptor, Serotonin, 5-HT2A/analysis/deficiency/genetics/*metabolism ; Receptors, Metabotropic Glutamate/analysis/antagonists & ; inhibitors/genetics/*metabolism ; Schizophrenia/metabolism ; Signal Transduction/drug effects ; Up-Regulation
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  • 74
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    Nature Publishing Group (NPG)
    Publication Date: 2008-08-08
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2008 Aug 7;454(7205):667. doi: 10.1038/454667b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18685646" target="_blank"〉PubMed〈/a〉
    Keywords: Drug Industry/*ethics ; *Federal Government ; Humans ; Italy
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  • 75
    Publication Date: 2008-08-01
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kanner, Baruch I -- England -- Nature. 2008 Jul 31;454(7204):593-4. doi: 10.1038/454593a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18668099" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/*metabolism ; Galactose/metabolism ; *Ion Transport ; Models, Molecular ; Protein Structure, Tertiary ; Sodium/metabolism ; Sodium-Glucose Transport Proteins/*chemistry/*metabolism
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  • 76
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    Nature Publishing Group (NPG)
    Publication Date: 2008-07-25
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2008 Jul 24;454(7203):381. doi: 10.1038/454381e.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18650879" target="_blank"〉PubMed〈/a〉
    Keywords: AIDS Vaccines ; Acquired Immunodeficiency Syndrome/*economics ; Biomedical Research/*economics ; *Federal Government ; Humans ; Research Support as Topic ; United States
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  • 77
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    Publication Date: 2008-07-25
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2008 Jul 24;454(7203):368. doi: 10.1038/454368a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18650857" target="_blank"〉PubMed〈/a〉
    Keywords: *Environmental Monitoring ; *Federal Government ; *Greenhouse Effect ; United States
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  • 78
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    Publication Date: 2008-11-14
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Witze, Alexandra -- England -- Nature. 2008 Nov 13;456(7219):146-7. doi: 10.1038/456146a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19005517" target="_blank"〉PubMed〈/a〉
    Keywords: *Federal Government ; *Greenhouse Effect ; *Policy Making ; United States
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  • 79
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    Publication Date: 2008-09-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Witze, Alexandra -- England -- Nature. 2008 Sep 25;455(7212):442-5. doi: 10.1038/455442a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18818623" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Embryo Research ; *Federal Government ; Greenhouse Effect ; Humans ; Science/economics/*organization & administration/trends ; Space Flight/trends ; Stem Cells ; Technology/economics/*organization & administration/trends ; United States
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  • 80
    Publication Date: 2008-02-22
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Witze, Alexandra -- England -- Nature. 2008 Feb 21;451(7181):875. doi: 10.1038/451875a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18288150" target="_blank"〉PubMed〈/a〉
    Keywords: *Federal Government ; Lobbying ; *Research Personnel ; Science/*organization & administration ; United States
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  • 81
    Publication Date: 2008-11-07
    Description: The recent emergence of highly pathogenic avian (H5N1) influenza viruses, their epizootic and panzootic nature, and their association with lethal human infections have raised significant global health concerns. Several studies have underlined the importance of non-structural protein NS1 in the increased pathogenicity and virulence of these strains. NS1, which consists of two domains-a double-stranded RNA (dsRNA) binding domain and the effector domain, separated through a linker-is an antagonist of antiviral type-I interferon response in the host. Here we report the X-ray structure of the full-length NS1 from an H5N1 strain (A/Vietnam/1203/2004) that was associated with 60% of human deaths in an outbreak in Vietnam. Compared to the individually determined structures of the RNA binding domain and the effector domain from non-H5N1 strains, the RNA binding domain within H5N1 NS1 exhibits modest structural changes, while the H5N1 effector domain shows significant alteration, particularly in the dimeric interface. Although both domains in the full-length NS1 individually participate in dimeric interactions, an unexpected finding is that these interactions result in the formation of a chain of NS1 molecules instead of distinct dimeric units. Three such chains in the crystal interact with one another extensively to form a tubular organization of similar dimensions to that observed in the cryo-electron microscopy images of NS1 in the presence of dsRNA. The tubular oligomeric organization of NS1, in which residues implicated in dsRNA binding face a 20-A-wide central tunnel, provides a plausible mechanism for how NS1 sequesters varying lengths of dsRNA, to counter cellular antiviral dsRNA response pathways, while simultaneously interacting with other cellular ligands during an infection.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2798118/" 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/PMC2798118/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bornholdt, Zachary A -- Prasad, B V Venkataram -- AI36040/AI/NIAID NIH HHS/ -- R37 AI036040/AI/NIAID NIH HHS/ -- R37 AI036040-21/AI/NIAID NIH HHS/ -- RR002250/RR/NCRR NIH HHS/ -- England -- Nature. 2008 Dec 18;456(7224):985-8. doi: 10.1038/nature07444. Epub 2008 Nov 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Virology and Microbiology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18987632" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Cryoelectron Microscopy ; Crystallography, X-Ray ; Humans ; Influenza A Virus, H5N1 Subtype/*chemistry/*pathogenicity ; Influenza, Human/epidemiology/virology ; Models, Molecular ; Protein Multimerization ; Protein Structure, Tertiary ; Vietnam/epidemiology ; Viral Nonstructural Proteins/*chemistry/ultrastructure ; Virulence ; Virulence Factors
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  • 82
    Publication Date: 2008-09-17
    Description: Hedgehog (Hh) proteins specify tissue pattern in metazoan embryos by forming gradients that emanate from discrete sites of expression and elicit concentration-dependent cellular differentiation or proliferation responses. Cellular responses to Hh and the movement of Hh through tissues are both precisely regulated, and abnormal Hh signalling has been implicated in human birth defects and cancer. Hh signalling is mediated by its amino-terminal domain (HhN), which is dually lipidated and secreted as part of a multivalent lipoprotein particle. Reception of the HhN signal is modulated by several cell-surface proteins on responding cells, including Patched (Ptc), Smoothened (Smo), Ihog (known as CDO or CDON in mammals) and the vertebrate-specific proteins Hip (also known as Hhip) and Gas1 (ref. 11). Drosophila Ihog and its vertebrate homologues CDO and BOC contain multiple immunoglobulin and fibronectin type III (FNIII) repeats, and the first FNIII repeat of Ihog binds Drosophila HhN in a heparin-dependent manner. Surprisingly, pull-down experiments suggest that a mammalian Sonic hedgehog N-terminal domain (ShhN) binds a non-orthologous FNIII repeat of CDO. Here we report biochemical, biophysical and X-ray structural studies of a complex between ShhN and the third FNIII repeat of CDO. We show that the ShhN-CDO interaction is completely unlike the HhN-Ihog interaction and requires calcium, which binds at a previously undetected site on ShhN. This site is conserved in nearly all Hh proteins and is a hotspot for mediating interactions between ShhN and CDO, Ptc, Hip and Gas1. Mutations in vertebrate Hh proteins causing holoprosencephaly and brachydactyly type A1 map to this calcium-binding site and disrupt interactions with these partners.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2679680/" 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/PMC2679680/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McLellan, Jason S -- Zheng, Xiaoyan -- Hauk, Glenn -- Ghirlando, Rodolfo -- Beachy, Philip A -- Leahy, Daniel J -- R01 HD055545/HD/NICHD NIH HHS/ -- Z99 DK999999/Intramural NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Oct 16;455(7215):979-83. doi: 10.1038/nature07358. Epub 2008 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18794898" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Calcium/metabolism ; Cell Adhesion Molecules/chemistry/metabolism ; Cell Cycle Proteins/chemistry/metabolism ; Cell Line ; *Conserved Sequence ; Crystallography, X-Ray ; Drosophila Proteins/*chemistry/*metabolism ; Drosophila melanogaster/chemistry ; Fibronectins/chemistry ; GPI-Linked Proteins ; Hedgehog Proteins/*chemistry/genetics/*metabolism ; Humans ; Immunoglobulin G/chemistry/metabolism ; Membrane Glycoproteins/*chemistry/*metabolism ; Membrane Proteins/chemistry/metabolism ; Mice ; Models, Molecular ; Protein Binding/genetics ; Protein Structure, Tertiary ; Receptors, Cell Surface/*chemistry/*metabolism ; *Sequence Homology, Amino Acid ; Signal Transduction ; Tumor Suppressor Proteins/chemistry/metabolism
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  • 83
    Publication Date: 2008-06-13
    Description: In modern organisms, protein enzymes are solely responsible for the aminoacylation of transfer RNA. However, the evolution of protein synthesis in the RNA world required RNAs capable of catalysing this reaction. Ribozymes that aminoacylate RNA by using activated amino acids have been discovered through selection in vitro. Flexizyme is a 45-nucleotide ribozyme capable of charging tRNA in trans with various activated l-phenylalanine derivatives. In addition to a more than 10(5) rate enhancement and more than 10(4)-fold discrimination against some non-cognate amino acids, this ribozyme achieves good regioselectivity: of all the hydroxyl groups of a tRNA, it exclusively aminoacylates the terminal 3'-OH. Here we report the 2.8-A resolution structure of flexizyme fused to a substrate RNA. Together with randomization of ribozyme core residues and reselection, this structure shows that very few nucleotides are needed for the aminoacylation of specific tRNAs. Although it primarily recognizes tRNA through base-pairing with the CCA terminus of the tRNA molecule, flexizyme makes numerous local interactions to position the acceptor end of tRNA precisely. A comparison of two crystallographically independent flexizyme conformations, only one of which appears capable of binding activated phenylalanine, suggests that this ribozyme may achieve enhanced specificity by coupling active-site folding to tRNA docking. Such a mechanism would be reminiscent of the mutually induced fit of tRNA and protein employed by some aminoacyl-tRNA synthetases to increase specificity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xiao, Hong -- Murakami, Hiroshi -- Suga, Hiroaki -- Ferre-D'Amare, Adrian R -- England -- Nature. 2008 Jul 17;454(7202):358-61. doi: 10.1038/nature07033. Epub 2008 Jun 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109-1024, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18548004" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acyl-tRNA Synthetases/chemistry/metabolism ; Base Sequence ; Binding Sites ; Escherichia coli/enzymology ; Models, Molecular ; Nucleic Acid Conformation ; Protein Folding ; Protein Structure, Tertiary ; RNA, Catalytic/chemistry/genetics/*metabolism ; RNA, Transfer/chemistry/genetics/*metabolism ; *Transfer RNA Aminoacylation
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  • 84
    Publication Date: 2008-01-25
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Requena, Jaime -- England -- Nature. 2008 Jan 24;451(7177):395. doi: 10.1038/451395d.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18216828" target="_blank"〉PubMed〈/a〉
    Keywords: *Federal Government ; Financing, Organized ; Research Support as Topic ; Social Sciences/*economics/*trends ; Students ; Venezuela
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  • 85
    Publication Date: 2008-10-17
    Description: Diatoms are photosynthetic secondary endosymbionts found throughout marine and freshwater environments, and are believed to be responsible for around one-fifth of the primary productivity on Earth. The genome sequence of the marine centric diatom Thalassiosira pseudonana was recently reported, revealing a wealth of information about diatom biology. Here we report the complete genome sequence of the pennate diatom Phaeodactylum tricornutum and compare it with that of T. pseudonana to clarify evolutionary origins, functional significance and ubiquity of these features throughout diatoms. In spite of the fact that the pennate and centric lineages have only been diverging for 90 million years, their genome structures are dramatically different and a substantial fraction of genes ( approximately 40%) are not shared by these representatives of the two lineages. Analysis of molecular divergence compared with yeasts and metazoans reveals rapid rates of gene diversification in diatoms. Contributing factors include selective gene family expansions, differential losses and gains of genes and introns, and differential mobilization of transposable elements. Most significantly, we document the presence of hundreds of genes from bacteria. More than 300 of these gene transfers are found in both diatoms, attesting to their ancient origins, and many are likely to provide novel possibilities for metabolite management and for perception of environmental signals. These findings go a long way towards explaining the incredible diversity and success of the diatoms in contemporary oceans.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bowler, Chris -- Allen, Andrew E -- Badger, Jonathan H -- Grimwood, Jane -- Jabbari, Kamel -- Kuo, Alan -- Maheswari, Uma -- Martens, Cindy -- Maumus, Florian -- Otillar, Robert P -- Rayko, Edda -- Salamov, Asaf -- Vandepoele, Klaas -- Beszteri, Bank -- Gruber, Ansgar -- Heijde, Marc -- Katinka, Michael -- Mock, Thomas -- Valentin, Klaus -- Verret, Frederic -- Berges, John A -- Brownlee, Colin -- Cadoret, Jean-Paul -- Chiovitti, Anthony -- Choi, Chang Jae -- Coesel, Sacha -- De Martino, Alessandra -- Detter, J Chris -- Durkin, Colleen -- Falciatore, Angela -- Fournet, Jerome -- Haruta, Miyoshi -- Huysman, Marie J J -- Jenkins, Bethany D -- Jiroutova, Katerina -- Jorgensen, Richard E -- Joubert, Yolaine -- Kaplan, Aaron -- Kroger, Nils -- Kroth, Peter G -- La Roche, Julie -- Lindquist, Erica -- Lommer, Markus -- Martin-Jezequel, Veronique -- Lopez, Pascal J -- Lucas, Susan -- Mangogna, Manuela -- McGinnis, Karen -- Medlin, Linda K -- Montsant, Anton -- Oudot-Le Secq, Marie-Pierre -- Napoli, Carolyn -- Obornik, Miroslav -- Parker, Micaela Schnitzler -- Petit, Jean-Louis -- Porcel, Betina M -- Poulsen, Nicole -- Robison, Matthew -- Rychlewski, Leszek -- Rynearson, Tatiana A -- Schmutz, Jeremy -- Shapiro, Harris -- Siaut, Magali -- Stanley, Michele -- Sussman, Michael R -- Taylor, Alison R -- Vardi, Assaf -- von Dassow, Peter -- Vyverman, Wim -- Willis, Anusuya -- Wyrwicz, Lucjan S -- Rokhsar, Daniel S -- Weissenbach, Jean -- Armbrust, E Virginia -- Green, Beverley R -- Van de Peer, Yves -- Grigoriev, Igor V -- England -- Nature. 2008 Nov 13;456(7219):239-44. doi: 10.1038/nature07410. Epub 2008 Oct 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CNRS UMR8186, Department of Biology, Ecole Normale Superieure, 46 rue d'Ulm, 75005 Paris, France. cbowler@biologie.ens.fr〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18923393" target="_blank"〉PubMed〈/a〉
    Keywords: DNA, Algal/analysis ; Diatoms/*genetics ; *Evolution, Molecular ; Genes, Bacterial/genetics ; Genome/*genetics ; Molecular Sequence Data ; Protein Structure, Tertiary ; Sequence Homology, Amino Acid ; Signal Transduction
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  • 86
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    Nature Publishing Group (NPG)
    Publication Date: 2008-12-19
    Description: The detection of electrical potentials across lipid bilayers by specialized membrane proteins is required for many fundamental cellular processes such as the generation and propagation of nerve impulses. These membrane proteins possess modular voltage-sensing domains, a notable example being the S1-S4 domains of voltage-activated ion channels. Ground-breaking structural studies on these domains explain how voltage sensors are designed and reveal important interactions with the surrounding lipid membrane. Although further structures are needed to understand the conformational changes that occur during voltage sensing, the available data help to frame several key concepts that are fundamental to the mechanism of voltage sensing.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629456/" 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/PMC2629456/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Swartz, Kenton J -- ZIA NS002945-13/Intramural NIH HHS/ -- England -- Nature. 2008 Dec 18;456(7224):891-7. doi: 10.1038/nature07620.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Porter Neuroscience Research Center, Molecular Physiology and Biophysics Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA. swartzk@ninds.nih.gov〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19092925" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Membrane/*metabolism ; Humans ; *Ion Channel Gating ; Membrane Lipids/*metabolism ; Membrane Proteins/*chemistry/*metabolism ; Movement ; Protein Structure, Tertiary
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  • 87
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    Nature Publishing Group (NPG)
    Publication Date: 2008-06-06
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2008 Jun 5;453(7196):697-8. doi: 10.1038/453697b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18528338" target="_blank"〉PubMed〈/a〉
    Keywords: Embryonic Stem Cells ; *Federal Government ; Greenhouse Effect ; Humans ; Nuclear Weapons/legislation & jurisprudence ; Science/*legislation & jurisprudence ; United States
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  • 88
    Publication Date: 2008-05-27
    Description: Members of the epidermal growth factor receptor (EGFR) or ErbB/HER family and their activating ligands are essential regulators of diverse developmental processes. Inappropriate activation of these receptors is a key feature of many human cancers, and its reversal is an important clinical goal. A natural secreted antagonist of EGFR signalling, called Argos, was identified in Drosophila. We showed previously that Argos functions by directly binding (and sequestering) growth factor ligands that activate EGFR. Here we describe the 1.6-A resolution crystal structure of Argos bound to an EGFR ligand. Contrary to expectations, Argos contains no EGF-like domain. Instead, a trio of closely related domains (resembling a three-finger toxin fold) form a clamp-like structure around the bound EGF ligand. Although structurally unrelated to the receptor, Argos mimics EGFR by using a bipartite binding surface to entrap EGF. The individual Argos domains share unexpected structural similarities with the extracellular ligand-binding regions of transforming growth factor-beta family receptors. The three-domain clamp of Argos also resembles the urokinase-type plasminogen activator (uPA) receptor, which uses a similar mechanism to engulf the EGF-like module of uPA. Our results indicate that undiscovered mammalian counterparts of Argos may exist among other poorly characterized structural homologues. In addition, the structures presented here define requirements for the design of artificial EGF-sequestering proteins that would be valuable anti-cancer therapeutics.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2526102/" 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/PMC2526102/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Klein, Daryl E -- Stayrook, Steven E -- Shi, Fumin -- Narayan, Kartik -- Lemmon, Mark A -- R01 CA079992/CA/NCI NIH HHS/ -- R01 CA079992-10/CA/NCI NIH HHS/ -- R01 CA125432/CA/NCI NIH HHS/ -- R01 CA125432-01A1/CA/NCI NIH HHS/ -- England -- Nature. 2008 Jun 26;453(7199):1271-5. doi: 10.1038/nature06978. Epub 2008 May 25.〈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/18500331" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Cell Line ; Crystallography, X-Ray ; Drosophila Proteins/*chemistry/*metabolism ; Drosophila melanogaster/*chemistry/cytology ; Epidermal Growth Factor/*chemistry/*metabolism ; Eye Proteins/*chemistry/*metabolism ; Humans ; Ligands ; Membrane Proteins/*chemistry/*metabolism ; Models, Molecular ; Nerve Tissue Proteins/*chemistry/*metabolism ; Protein Structure, Tertiary ; Receptor, Epidermal Growth Factor/antagonists & inhibitors/chemistry/*metabolism ; Receptors, Transforming Growth Factor beta/chemistry/metabolism ; Spodoptera
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  • 89
    Publication Date: 2008-10-04
    Description: HIV-1 protease processes the Gag and Gag-Pol polyproteins into mature structural and functional proteins, including itself, and is therefore indispensable for viral maturation. The mature protease is active only as a dimer with each subunit contributing catalytic residues. The full-length transframe region protease precursor appears to be monomeric yet undergoes maturation via intramolecular cleavage of a putative precursor dimer, concomitant with the appearance of mature-like catalytic activity. How such intramolecular cleavage can occur when the amino and carboxy termini of the mature protease are part of an intersubunit beta-sheet located distal from the active site is unclear. Here we visualize the early events in N-terminal autoprocessing using an inactive mini-precursor with a four-residue N-terminal extension that mimics the transframe region protease precursor. Using paramagnetic relaxation enhancement, a technique that is exquisitely sensitive to the presence of minor species, we show that the mini-precursor forms highly transient, lowly populated (3-5%) dimeric encounter complexes that involve the mature dimer interface but occupy a wide range of subunit orientations relative to the mature dimer. Furthermore, the occupancy of the mature dimer configuration constitutes a very small fraction of the self-associated species (accounting for the very low enzymatic activity of the protease precursor), and the N-terminal extension makes transient intra- and intersubunit contacts with the substrate binding site and is therefore available for autocleavage when the correct dimer orientation is sampled within the encounter complex ensemble.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2798589/" 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/PMC2798589/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tang, Chun -- Louis, John M -- Aniana, Annie -- Suh, Jeong-Yong -- Clore, G Marius -- ZIA DK029023-19/Intramural NIH HHS/ -- England -- Nature. 2008 Oct 2;455(7213):693-6. doi: 10.1038/nature07342.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Chemical Physics, Building 5, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18833280" target="_blank"〉PubMed〈/a〉
    Keywords: Dimerization ; HIV Protease/*chemistry/genetics/*metabolism ; HIV-1/*enzymology/genetics ; Models, Molecular ; Nuclear Magnetic Resonance, Biomolecular ; Protein Precursors/*chemistry/genetics/*metabolism ; *Protein Processing, Post-Translational ; Protein Structure, Tertiary ; Spin Labels ; gag Gene Products, Human Immunodeficiency Virus/chemistry/metabolism
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  • 90
    Publication Date: 2008-02-22
    Description: Glucose flux through the hexosamine biosynthetic pathway leads to the post-translational modification of cytoplasmic and nuclear proteins by O-linked beta-N-acetylglucosamine (O-GlcNAc). This tandem system serves as a nutrient sensor to couple systemic metabolic status to cellular regulation of signal transduction, transcription, and protein degradation. Here we show that O-GlcNAc transferase (OGT) harbours a previously unrecognized type of phosphoinositide-binding domain. After induction with insulin, phosphatidylinositol 3,4,5-trisphosphate recruits OGT from the nucleus to the plasma membrane, where the enzyme catalyses dynamic modification of the insulin signalling pathway by O-GlcNAc. This results in the alteration in phosphorylation of key signalling molecules and the attenuation of insulin signal transduction. Hepatic overexpression of OGT impairs the expression of insulin-responsive genes and causes insulin resistance and dyslipidaemia. These findings identify a molecular mechanism by which nutritional cues regulate insulin signalling through O-GlcNAc, and underscore the contribution of this modification to the aetiology of insulin resistance and type 2 diabetes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Xiaoyong -- Ongusaha, Pat P -- Miles, Philip D -- Havstad, Joyce C -- Zhang, Fengxue -- So, W Venus -- Kudlow, Jeffrey E -- Michell, Robert H -- Olefsky, Jerrold M -- Field, Seth J -- Evans, Ronald M -- P30 CA014195/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Feb 21;451(7181):964-9. doi: 10.1038/nature06668.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Gene Expression 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/18288188" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylglucosamine/metabolism/pharmacology ; Animals ; COS Cells ; Cell Membrane/metabolism ; Cercopithecus aethiops ; Insulin/pharmacology ; Insulin Resistance/*physiology ; Lipid Metabolism ; Liver/enzymology/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; N-Acetylglucosaminyltransferases/chemistry/genetics/*metabolism ; Phosphatidylinositol Phosphates/metabolism ; Phosphatidylinositols/*metabolism ; Phosphorylation/drug effects ; Protein Structure, Tertiary ; Protein Transport ; *Second Messenger Systems/drug effects
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  • 91
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    Nature Publishing Group (NPG)
    Publication Date: 2008-05-10
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2008 May 8;453(7192):133. doi: 10.1038/453133a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18464687" target="_blank"〉PubMed〈/a〉
    Keywords: *Federal Government ; France ; Research/economics/*organization & administration ; Universities/economics/*organization & administration
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  • 92
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    Nature Publishing Group (NPG)
    Publication Date: 2008-05-10
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2008 May 8;453(7192):133-4. doi: 10.1038/453133b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18464686" target="_blank"〉PubMed〈/a〉
    Keywords: Budgets/legislation & jurisprudence ; *Competitive Behavior ; Engineering/economics/standards ; *Federal Government ; Physics/economics/standards ; Research/*economics/legislation & jurisprudence/*standards ; United States
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 93
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    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2008-10-31
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yeager, Ashley -- England -- Nature. 2008 Oct 30;455(7217):1154-5. doi: 10.1038/4551154a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18971982" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line ; Embryo Research/economics/*legislation & jurisprudence ; *Embryonic Stem Cells/cytology ; *Federal Government ; Female ; Humans ; Michigan ; *State Government
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 94
    Publication Date: 2008-04-04
    Description: Multidrug resistance (MDR) is a serious complication during treatment of opportunistic fungal infections that frequently afflict immunocompromised individuals, such as transplant recipients and cancer patients undergoing cytotoxic chemotherapy. Improved knowledge of the molecular pathways controlling MDR in pathogenic fungi should facilitate the development of novel therapies to combat these intransigent infections. MDR is often caused by upregulation of drug efflux pumps by members of the fungal zinc-cluster transcription-factor family (for example Pdr1p orthologues). However, the molecular mechanisms are poorly understood. Here we show that Pdr1p family members in Saccharomyces cerevisiae and the human pathogen Candida glabrata directly bind to structurally diverse drugs and xenobiotics, resulting in stimulated expression of drug efflux pumps and induction of MDR. Notably, this is mechanistically similar to regulation of MDR in vertebrates by the PXR nuclear receptor, revealing an unexpected functional analogy of fungal and metazoan regulators of MDR. We have also uncovered a critical and specific role of the Gal11p/MED15 subunit of the Mediator co-activator and its activator-targeted KIX domain in antifungal/xenobiotic-dependent regulation of MDR. This detailed mechanistic understanding of a fungal nuclear receptor-like gene regulatory pathway provides novel therapeutic targets for the treatment of multidrug-resistant fungal infections.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Thakur, Jitendra K -- Arthanari, Haribabu -- Yang, Fajun -- Pan, Shih-Jung -- Fan, Xiaochun -- Breger, Julia -- Frueh, Dominique P -- Gulshan, Kailash -- Li, Darrick K -- Mylonakis, Eleftherios -- Struhl, Kevin -- Moye-Rowley, W Scott -- Cormack, Brendan P -- Wagner, Gerhard -- Naar, Anders M -- A1046223/PHS HHS/ -- CA127990/CA/NCI NIH HHS/ -- EB2026/EB/NIBIB NIH HHS/ -- GM071449/GM/NIGMS NIH HHS/ -- GM30186/GM/NIGMS NIH HHS/ -- GM47467/GM/NIGMS NIH HHS/ -- GM49825/GM/NIGMS NIH HHS/ -- R01 CA127990/CA/NCI NIH HHS/ -- England -- Nature. 2008 Apr 3;452(7187):604-9. doi: 10.1038/nature06836.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18385733" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antifungal Agents/metabolism/pharmacology ; Candida glabrata/drug effects/genetics/*metabolism ; DNA-Binding Proteins/chemistry/genetics/metabolism ; *Drug Resistance, Fungal/genetics ; Fungal Proteins/chemistry/genetics/*metabolism ; *Gene Expression Regulation, Fungal/genetics ; Genes, Fungal/genetics ; Mediator Complex ; Multigene Family ; Protein Structure, Tertiary ; Receptors, Steroid/*metabolism ; Saccharomyces cerevisiae/drug effects/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/genetics/metabolism ; Trans-Activators/chemistry/genetics/metabolism ; Transcription Factors/metabolism ; Transcription, Genetic/genetics ; Xenobiotics/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 95
    Publication Date: 2008-08-16
    Description: Non-ribosomal peptide synthetases (NRPS) and polyketide synthases (PKS) found in bacteria, fungi and plants use two different types of thioesterases for the production of highly active biological compounds. Type I thioesterases (TEI) catalyse the release step from the assembly line of the final product where it is transported from one reaction centre to the next as a thioester linked to a 4'-phosphopantetheine (4'-PP) cofactor that is covalently attached to thiolation (T) domains. The second enzyme involved in the synthesis of these secondary metabolites, the type II thioesterase (TEII), is a crucial repair enzyme for the regeneration of functional 4'-PP cofactors of holo-T domains of NRPS and PKS systems. Mispriming of 4'-PP cofactors by acetyl- and short-chain acyl-residues interrupts the biosynthetic system. This repair reaction is very important, because roughly 80% of CoA, the precursor of the 4'-PP cofactor, is acetylated in bacteria. Here we report the three-dimensional structure of a type II thioesterase from Bacillus subtilis free and in complex with a T domain. Comparison with structures of TEI enzymes shows the basis for substrate selectivity and the different modes of interaction of TEII and TEI enzymes with T domains. Furthermore, we show that the TEII enzyme exists in several conformations of which only one is selected on interaction with its native substrate, a modified holo-T domain.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2854587/" 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/PMC2854587/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Koglin, Alexander -- Lohr, Frank -- Bernhard, Frank -- Rogov, Vladimir V -- Frueh, Dominique P -- Strieter, Eric R -- Mofid, Mohammad R -- Guntert, Peter -- Wagner, Gerhard -- Walsh, Christopher T -- Marahiel, Mohamed A -- Dotsch, Volker -- P01 GM047467/GM/NIGMS NIH HHS/ -- P01 GM047467-110009/GM/NIGMS NIH HHS/ -- P01 GM047467-12/GM/NIGMS NIH HHS/ -- P01 GM047467-13/GM/NIGMS NIH HHS/ -- P01 GM047467-14/GM/NIGMS NIH HHS/ -- P01 GM047467-15/GM/NIGMS NIH HHS/ -- P01 GM047467-16/GM/NIGMS NIH HHS/ -- P01 GM047467-160010/GM/NIGMS NIH HHS/ -- P01 GM047467-160012/GM/NIGMS NIH HHS/ -- P01 GM047467-17/GM/NIGMS NIH HHS/ -- P01 GM047467-170012/GM/NIGMS NIH HHS/ -- P41 EB002026/EB/NIBIB NIH HHS/ -- P41 EB002026-29/EB/NIBIB NIH HHS/ -- P41 EB002026-30/EB/NIBIB NIH HHS/ -- P41 EB002026-31/EB/NIBIB NIH HHS/ -- P41 EB002026-32/EB/NIBIB NIH HHS/ -- P41 EB002026-33/EB/NIBIB NIH HHS/ -- R01 AI042738/AI/NIAID NIH HHS/ -- R01 AI042738-09/AI/NIAID NIH HHS/ -- R01 GM020011/GM/NIGMS NIH HHS/ -- R01 GM020011-28/GM/NIGMS NIH HHS/ -- R01 GM020011-29/GM/NIGMS NIH HHS/ -- R01 GM020011-30/GM/NIGMS NIH HHS/ -- R01 GM020011-31/GM/NIGMS NIH HHS/ -- R01 GM020011-32/GM/NIGMS NIH HHS/ -- R01 GM020011-37/GM/NIGMS NIH HHS/ -- R01 GM020011-38/GM/NIGMS NIH HHS/ -- R01 GM049338/GM/NIGMS NIH HHS/ -- R01 GM049338-17/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Aug 14;454(7206):907-11. doi: 10.1038/nature07161.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes (CEF), J.W.-Goethe University, 60438 Frankfurt am Main, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18704089" target="_blank"〉PubMed〈/a〉
    Keywords: Bacillus subtilis/*enzymology ; Bacterial Proteins/biosynthesis/*chemistry/*metabolism ; Fatty Acid Synthases/*chemistry/*metabolism ; Models, Molecular ; Nuclear Magnetic Resonance, Biomolecular ; Peptide Synthases/biosynthesis/*chemistry/*metabolism ; Protein Interaction Domains and Motifs ; Protein Structure, Tertiary ; Thiolester Hydrolases/*chemistry/*metabolism
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  • 96
    Publication Date: 2008-01-19
    Description: Spastin, the most common locus for mutations in hereditary spastic paraplegias, and katanin are related microtubule-severing AAA ATPases involved in constructing neuronal and non-centrosomal microtubule arrays and in segregating chromosomes. The mechanism by which spastin and katanin break and destabilize microtubules is unknown, in part owing to the lack of structural information on these enzymes. Here we report the X-ray crystal structure of the Drosophila spastin AAA domain and provide a model for the active spastin hexamer generated using small-angle X-ray scattering combined with atomic docking. The spastin hexamer forms a ring with a prominent central pore and six radiating arms that may dock onto the microtubule. Helices unique to the microtubule-severing AAA ATPases surround the entrances to the pore on either side of the ring, and three highly conserved loops line the pore lumen. Mutagenesis reveals essential roles for these structural elements in the severing reaction. Peptide and antibody inhibition experiments further show that spastin may dismantle microtubules by recognizing specific features in the carboxy-terminal tail of tubulin. Collectively, our data support a model in which spastin pulls the C terminus of tubulin through its central pore, generating a mechanical force that destabilizes tubulin-tubulin interactions within the microtubule lattice. Our work also provides insights into the structural defects in spastin that arise from mutations identified in hereditary spastic paraplegia patients.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2882799/" 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/PMC2882799/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Roll-Mecak, Antonina -- Vale, Ronald D -- K99 NS057934-01/NS/NINDS NIH HHS/ -- K99 NS057934-02/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Jan 17;451(7176):363-7. doi: 10.1038/nature06482.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18202664" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/antagonists & ; inhibitors/*chemistry/*genetics/*metabolism ; Animals ; Drosophila Proteins/antagonists & inhibitors/*chemistry/genetics/*metabolism ; Humans ; Microtubules/chemistry/*metabolism ; Models, Biological ; Models, Molecular ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Scattering, Small Angle ; Spastic Paraplegia, Hereditary/*genetics ; Structure-Activity Relationship ; Substrate Specificity ; Tubulin/chemistry/metabolism ; X-Ray Diffraction
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  • 97
    Publication Date: 2008-05-03
    Description: During infection by Gram-negative pathogenic bacteria, the type III secretion system (T3SS) is assembled to allow for the direct transmission of bacterial virulence effectors into the host cell. The T3SS system is characterized by a series of prominent multi-component rings in the inner and outer bacterial membranes, as well as a translocation pore in the host cell membrane. These are all connected by a series of polymerized tubes that act as the direct conduit for the T3SS proteins to pass through to the host cell. During assembly of the T3SS, as well as the evolutionarily related flagellar apparatus, a post-translational cleavage event within the inner membrane proteins EscU/FlhB is required to promote a secretion-competent state. These proteins have long been proposed to act as a part of a molecular switch, which would regulate the appropriate chronological secretion of the various T3SS apparatus components during assembly and subsequently the transported virulence effectors. Here we show that a surface type II beta-turn in the Escherichia coli protein EscU undergoes auto-cleavage by a mechanism involving cyclization of a strictly conserved asparagine residue. Structural and in vivo analysis of point and deletion mutations illustrates the subtle conformational effects of auto-cleavage in modulating the molecular features of a highly conserved surface region of EscU, a potential point of interaction with other T3SS components at the inner membrane. In addition, this work provides new structural insight into the distinct conformational requirements for a large class of self-cleaving reactions involving asparagine cyclization.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zarivach, Raz -- Deng, Wanyin -- Vuckovic, Marija -- Felise, Heather B -- Nguyen, Hai V -- Miller, Samuel I -- Finlay, B Brett -- Strynadka, Natalie C J -- 5R01 AI030479/AI/NIAID NIH HHS/ -- R01 AI030479/AI/NIAID NIH HHS/ -- U54 AI057141/AI/NIAID NIH HHS/ -- England -- Nature. 2008 May 1;453(7191):124-7. doi: 10.1038/nature06832.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, and the Center for Blood Research, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18451864" target="_blank"〉PubMed〈/a〉
    Keywords: Asparagine/chemistry/metabolism ; Circular Dichroism ; Crystallography, X-Ray ; Cyclization ; Enteropathogenic Escherichia coli/*chemistry/*metabolism/pathogenicity ; Escherichia coli Proteins/*chemistry/genetics/*metabolism ; Models, Chemical ; Models, Molecular ; Protein Structure, Tertiary ; Salmonella typhimurium/genetics/metabolism ; Virulence Factors/metabolism
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  • 98
    Publication Date: 2008-12-05
    Description: Species-specific recognition between the egg extracellular matrix (zona pellucida) and sperm is the first, crucial step of mammalian fertilization. Zona pellucida filament components ZP3 and ZP2 act as sperm receptors, and mice lacking either of the corresponding genes produce oocytes without a zona pellucida and are completely infertile. Like their counterparts in the vitelline envelope of non-mammalian eggs and many other secreted eukaryotic proteins, zona pellucida subunits polymerize using a 'zona pellucida (ZP) domain' module, whose conserved amino-terminal part (ZP-N) was suggested to constitute a domain of its own. No atomic structure has been reported for ZP domain proteins, and there is no structural information on any conserved vertebrate protein that is essential for fertilization and directly involved in egg-sperm binding. Here we describe the 2.3 angstrom (A) resolution structure of the ZP-N fragment of mouse primary sperm receptor ZP3. The ZP-N fold defines a new immunoglobulin superfamily subtype with a beta-sheet extension characterized by an E' strand and an invariant tyrosine residue implicated in polymerization. The structure strongly supports the presence of ZP-N repeats within the N-terminal region of ZP2 and other vertebrate zona pellucida/vitelline envelope proteins, with implications for overall egg coat architecture, the post-fertilization block to polyspermy and speciation. Moreover, it provides an important framework for understanding human diseases caused by mutations in ZP domain proteins and developing new methods of non-hormonal contraception.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Monne, Magnus -- Han, Ling -- Schwend, Thomas -- Burendahl, Sofia -- Jovine, Luca -- G0500367/Medical Research Council/United Kingdom -- England -- Nature. 2008 Dec 4;456(7222):653-7. doi: 10.1038/nature07599.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Karolinska Institutet, Department of Biosciences and Nutrition, Halsovagen 7, SE-141 57 Huddinge, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19052627" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Binding Sites ; CHO Cells ; Conserved Sequence ; Cricetinae ; Cricetulus ; Crystallization ; Crystallography, X-Ray ; Egg Proteins/*chemistry/genetics/*metabolism ; Female ; Male ; Membrane Glycoproteins/*chemistry/genetics/*metabolism ; Mice ; Models, Molecular ; Molecular Sequence Data ; Ovum/*chemistry/*metabolism ; Peptide Fragments/chemistry/genetics/metabolism ; Protein Folding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Receptors, Cell Surface/*chemistry/genetics/*metabolism ; Repetitive Sequences, Amino Acid ; Spermatozoa/metabolism
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  • 99
    facet.materialart.
    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2008-06-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brumfiel, Geoff -- England -- Nature. 2008 Jun 26;453(7199):1150-1. doi: 10.1038/4531150a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18580908" target="_blank"〉PubMed〈/a〉
    Keywords: *Federal Government ; Great Britain ; Humans ; Research Support as Topic/economics/*legislation & jurisprudence/*organization & ; administration/trends
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 100
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    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2008-11-28
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tollefson, Jeff -- England -- Nature. 2008 Nov 27;456(7221):428-9. doi: 10.1038/456428a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19037280" target="_blank"〉PubMed〈/a〉
    Keywords: *Congresses as Topic/trends ; Conservation of Natural Resources/trends ; *Federal Government ; Forestry/legislation & jurisprudence ; *Greenhouse Effect ; International Cooperation ; Poland ; United States ; United States Environmental Protection Agency/legislation & jurisprudence
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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