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  • 1
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    Structure and mechanism of a Na+-independent amino acid transporter (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-07-18
    Description: Amino acid, polyamine, and organocation (APC) transporters are secondary transporters that play essential roles in nutrient uptake, neurotransmitter recycling, ionic homeostasis, and regulation of cell volume. Here, we present the crystal structure of apo-ApcT, a proton-coupled broad-specificity amino acid transporter, at 2.35 angstrom resolution. The structure contains 12 transmembrane helices, with the first 10 consisting of an inverted structural repeat of 5 transmembrane helices like the leucine transporter LeuT. The ApcT structure reveals an inward-facing, apo state and an amine moiety of lysine-158 located in a position equivalent to the sodium ion site Na2 of LeuT. We propose that lysine-158 is central to proton-coupled transport and that the amine group serves the same functional role as the Na2 ion in LeuT, thus demonstrating common principles among proton- and sodium-coupled transporters.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2851542/" 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/PMC2851542/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shaffer, Paul L -- Goehring, April -- Shankaranarayanan, Aruna -- Gouaux, Eric -- R01 MH070039/MH/NIMH NIH HHS/ -- R01 MH070039-05/MH/NIMH NIH HHS/ -- T32 GM008281/GM/NIGMS NIH HHS/ -- T32 GM008281-17/GM/NIGMS NIH HHS/ -- U54 GM075026/GM/NIGMS NIH HHS/ -- U54 GM075026-040002/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2009 Aug 21;325(5943):1010-4. doi: 10.1126/science.1176088. Epub 2009 Jul 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vollum Institute, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19608859" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Amino Acid Transport Systems/*chemistry/*metabolism ; Amino Acids/metabolism ; Antiporters/chemistry ; Apoproteins/chemistry/metabolism ; Archaeal Proteins/*chemistry/*metabolism ; Crystallization ; Crystallography, X-Ray ; Escherichia coli Proteins/chemistry ; Methanococcus/*chemistry ; Models, Molecular ; Molecular Sequence Data ; Protein Conformation ; Protein Folding ; Protein Structure, Secondary ; Protons ; Sodium/metabolism ; Substrate Specificity
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    Structural basis for action by diverse antidepressants on biogenic amine transporters (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-10-15
    Description: The biogenic amine transporters (BATs) regulate endogenous neurotransmitter concentrations and are targets for a broad range of therapeutic agents including selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs). Because eukaryotic BATs are recalcitrant to crystallographic analysis, our understanding of the mechanism of these inhibitors and antidepressants is limited. LeuT is a bacterial homologue of BATs and has proven to be a valuable paradigm for understanding relationships between their structure and function. However, because only approximately 25% of the amino acid sequence of LeuT is in common with that of BATs, and as LeuT is a promiscuous amino acid transporter, it does not recapitulate the pharmacological properties of BATs. Indeed, SSRIs and TCAs bind in the extracellular vestibule of LeuT and act as non-competitive inhibitors of transport. By contrast, multiple studies demonstrate that both TCAs and SSRIs are competitive inhibitors for eukaryotic BATs and bind to the primary binding pocket. Here we engineered LeuT to harbour human BAT-like pharmacology by mutating key residues around the primary binding pocket. The final LeuBAT mutant binds the SSRI sertraline with a binding constant of 18 nM and displays high-affinity binding to a range of SSRIs, SNRIs and a TCA. We determined 12 crystal structures of LeuBAT in complex with four classes of antidepressants. The chemically diverse inhibitors have a remarkably similar mode of binding in which they straddle transmembrane helix (TM) 3, wedge between TM3/TM8 and TM1/TM6, and lock the transporter in a sodium- and chloride-bound outward-facing open conformation. Together, these studies define common and simple principles for the action of SSRIs, SNRIs and TCAs on BATs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904662/" 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/PMC3904662/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Hui -- Goehring, April -- Wang, Kevin H -- Penmatsa, Aravind -- Ressler, Ryan -- Gouaux, Eric -- R37 MH070039/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Nov 7;503(7474):141-5. doi: 10.1038/nature12648. Epub 2013 Oct 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24121440" target="_blank"〉PubMed〈/a〉
    Keywords: Antidepressive Agents, Second-Generation/metabolism/*pharmacology ; Antidepressive Agents, Tricyclic/metabolism/*pharmacology ; Bacterial Proteins/antagonists & inhibitors/chemistry/genetics/metabolism ; Binding, Competitive/drug effects ; Biogenic Amines/*metabolism ; Chlorides/metabolism ; Crystallography, X-Ray ; Humans ; Mazindol/metabolism/pharmacology ; Models, Molecular ; Mutation ; Norepinephrine/metabolism ; *Plasma Membrane Neurotransmitter Transport Proteins/antagonists & ; inhibitors/chemistry/genetics/metabolism ; Protein Conformation/drug effects ; Recombinant Fusion Proteins/*chemistry/genetics/metabolism ; Reproducibility of Results ; Serotonin Plasma Membrane Transport Proteins/*chemistry/genetics/*metabolism ; Serotonin Uptake Inhibitors/metabolism/*pharmacology ; Sertraline/metabolism/pharmacology ; Sodium/metabolism ; Structure-Activity Relationship
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    NMDA receptor structures reveal subunit arrangement and pore architecture (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-07-11
    Description: N-methyl-d-aspartate (NMDA) receptors are Hebbian-like coincidence detectors, requiring binding of glycine and glutamate in combination with the relief of voltage-dependent magnesium block to open an ion conductive pore across the membrane bilayer. Despite the importance of the NMDA receptor in the development and function of the brain, a molecular structure of an intact receptor has remained elusive. Here we present X-ray crystal structures of the Xenopus laevis GluN1-GluN2B NMDA receptor with the allosteric inhibitor, Ro25-6981, partial agonists and the ion channel blocker, MK-801. Receptor subunits are arranged in a 1-2-1-2 fashion, demonstrating extensive interactions between the amino-terminal and ligand-binding domains. The transmembrane domains harbour a closed-blocked ion channel, a pyramidal central vestibule lined by residues implicated in binding ion channel blockers and magnesium, and a approximately twofold symmetric arrangement of ion channel pore loops. These structures provide new insights into the architecture, allosteric coupling and ion channel function of NMDA receptors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4263351/" 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/PMC4263351/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Chia-Hsueh -- Lu, Wei -- Michel, Jennifer Carlisle -- Goehring, April -- Du, Juan -- Song, Xianqiang -- Gouaux, Eric -- R37 NS038631/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jul 10;511(7508):191-7. doi: 10.1038/nature13548. Epub 2014 Jun 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA [2]. ; 1] Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA [2] Howard Hughes Medical Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA. ; Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25008524" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Dizocilpine Maleate/chemistry ; Ion Channels/chemistry ; Ligands ; *Models, Molecular ; Phenols ; Piperidines/chemistry ; Protein Binding ; Protein Structure, Tertiary ; Protein Subunits/chemistry ; Receptors, N-Methyl-D-Aspartate/*chemistry ; Xenopus laevis/*physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 4
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    Structure and Mechanism of a Na+-Independent Amino Acid Transporter (2009)
    American Association for the Advancement of Science
    Details
    Publication Date: 2009-07-16
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science
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