دورية أكاديمية
Structure and allosteric inhibition mechanism of excitatory amino acid transporter 1
| العنوان: | Structure and allosteric inhibition mechanism of excitatory amino acid transporter 1 |
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| المؤلفون: | Canul-Tec, Juan, Assal, Reda, Cirri, Erica, Legrand, Pierre, Brier, Sébastien, Chamot-Rooke, Julia, Reyes, Nicolas |
| المساهمون: | Mécanismes moléculaires du transport membranaire - Molecular mechanisms of membrane transport, Institut Pasteur Paris (IP)-Centre National de la Recherche Scientifique (CNRS), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology (UTechS MSBio), Institut Pasteur Paris (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), The work was funded by the ERC Starting grant 309657 (N.R.). Further support from G5 Institut Pasteur funds (N.R.), CACSICE grant (ANR-11-EQPX-008), and CNRS UMR3528 (N.R., J.C.-R.) is acknowledged., We thank O. Boudker for comments on the manuscript and discussion on consensus mutagenesis, P. V. Krasteva for comments on the manuscript, A. Haouz and the staff at the crystallogenesis core facility of the Institut Pasteur for assistance with crystallization screens, Staff at Synchrotron SOLEIL and the European Synchrotron Radiation Facility for assistance with data collection, D. O’Brien for discussion of HDX results., ANR-11-EQPX-0008,CACSICE,Centre d'analyse de systèmes complexes dans les environnements complexes(2011), European Project: 309657,EC:FP7:ERC,ERC-2012-StG_20111109,HEAATS(2012) |
| المصدر: | ISSN: 0028-0836. |
| بيانات النشر: | HAL CCSD Nature Publishing Group |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Membrane proteins, Molecular neuroscience, Permeation and transport, MESH: Allosteric Regulation, MESH: Allosteric Site, MESH: Crystallization, MESH: Crystallography, X-Ray, MESH: Deuterium Exchange Measurement, MESH: Excitatory Amino Acid Transporter 1, MESH: Humans, MESH: Mass Spectrometry, MESH: Models, Molecular, MESH: Protein Domains, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics |
| الوصف: | International audience ; Human members of the solute carrier 1 (SLC1) family of transporters take up excitatory neurotransmitters in the brain and amino acids in peripheral organs. Dysregulation of the function of SLC1 transporters is associated with neurodegenerative disorders and cancer. Here we present crystal structures of a thermostabilized human SLC1 transporter, the excitatory amino acid transporter 1 (EAAT1), with and without allosteric and competitive inhibitors bound. The structures reveal architectural features of the human transporters, such as intra- and extracellular domains that have potential roles in transport function, regulation by lipids and post-translational modifications. The coordination of the allosteric inhibitor in the structures and the change in the transporter dynamics measured by hydrogen-deuterium exchange mass spectrometry reveal a mechanism of inhibition, in which the transporter is locked in the outward-facing states of the transport cycle. Our results provide insights into the molecular mechanisms underlying the function and pharmacology of human SLC1 transporters. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/28424515; info:eu-repo/grantAgreement/EC/FP7/309657/EU/Molecular bases of human excitatory neurotransmitter transport across the plasma membrane/HEAATS; pasteur-01655604; https://hal-pasteur.archives-ouvertes.fr/pasteur-01655604Test; https://hal-pasteur.archives-ouvertes.fr/pasteur-01655604/documentTest; https://hal-pasteur.archives-ouvertes.fr/pasteur-01655604/file/Canul-Tech-etal_nature_accepted_HAL.pdfTest; PUBMED: 28424515; PUBMEDCENTRAL: PMC5410168 |
| DOI: | 10.1038/nature22064 |
| الإتاحة: | https://doi.org/10.1038/nature22064Test https://hal-pasteur.archives-ouvertes.fr/pasteur-01655604Test https://hal-pasteur.archives-ouvertes.fr/pasteur-01655604/documentTest https://hal-pasteur.archives-ouvertes.fr/pasteur-01655604/file/Canul-Tech-etal_nature_accepted_HAL.pdfTest |
| حقوق: | http://creativecommons.org/licenses/by-nc-saTest/ ; info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.574D5196 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/nature22064 |
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