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dc.contributor.authorBrams, Marijke
dc.contributor.authorGovaerts, Cedric
dc.contributor.authorKambara, Kumiko
dc.contributor.authorPrice, Kerry L
dc.contributor.authorSpurny, Radovan
dc.contributor.authorGharpure, Anant
dc.contributor.authorPardon, Els
dc.contributor.authorEvans, Genevieve L
dc.contributor.authorBertrand, Daniel
dc.contributor.authorLummis, Sarah CR
dc.contributor.authorHibbs, Ryan E
dc.contributor.authorSteyaert, Jan
dc.contributor.authorUlens, Chris
dc.date.accessioned2020-02-13T05:05:08Z
dc.date.available2020-02-13T05:05:08Z
dc.date.issued2020-01-28
dc.date.submitted2019-08-30
dc.identifier.other51511
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/302091
dc.descriptionFunder: Instruct-ERIC
dc.description.abstractPentameric ligand-gated ion channels (pLGICs) or Cys-loop receptors are involved in fast synaptic signaling in the nervous system. Allosteric modulators bind to sites that are remote from the neurotransmitter binding site, but modify coupling of ligand binding to channel opening. In this study, we developed nanobodies (single domain antibodies), which are functionally active as allosteric modulators, and solved co-crystal structures of the prokaryote (Erwinia) channel ELIC bound either to a positive or a negative allosteric modulator. The allosteric nanobody binding sites partially overlap with those of small molecule modulators, including a vestibule binding site that is not accessible in some pLGICs. Using mutagenesis, we extrapolate the functional importance of the vestibule binding site to the human 5-HT3 receptor, suggesting a common mechanism of modulation in this protein and ELIC. Thus we identify key elements of allosteric binding sites, and extend drug design possibilities in pLGICs with an accessible vestibule site.
dc.languageen
dc.publishereLife Sciences Publications, Ltd
dc.rightsAttribution 4.0 International (CC BY 4.0)en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectResearch Article
dc.subjectNeuroscience
dc.subjectStructural Biology and Molecular Biophysics
dc.subjectligand-gated ion channels
dc.subjectstructural biology
dc.subjectallosteric modulation
dc.subjectHuman
dc.titleModulation of the Erwinia ligand-gated ion channel (ELIC) and the 5-HT 3 receptor via a common vestibule site
dc.typeArticle
dc.date.updated2020-02-13T05:05:08Z
prism.publicationNameeLife
prism.volume9
dc.identifier.doi10.17863/CAM.49166
dcterms.dateAccepted2020-01-27
rioxxterms.versionofrecord10.7554/elife.51511
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
datacite.contributor.supervisoreditor: Czajkowski, Cynthia M
datacite.contributor.supervisorsenior_editor: Swartz, Kenton J
dc.contributor.orcidGharpure, Anant [0000-0002-4458-359X]
dc.contributor.orcidEvans, Genevieve L [0000-0002-8612-9539]
dc.contributor.orcidSteyaert, Jan [0000-0002-3825-874X]
dc.contributor.orcidUlens, Chris [0000-0002-8202-5281]
dc.identifier.eissn2050-084X
pubs.funder-project-idAgentschap Innoveren en Ondernemen (1200261)
pubs.funder-project-idFonds Wetenschappelijk Onderzoek (G.0762.13)
pubs.funder-project-idKU Leuven (OT/13/095)
pubs.funder-project-idKU Leuven (C32/16/035)
pubs.funder-project-idKU Leuven (C14/17/093)
pubs.funder-project-idNational Institutes of Health (DA047325)
pubs.funder-project-idNational Institutes of Health (DA042072)
pubs.funder-project-idNational Institutes of Health (NS095899)


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Attribution 4.0 International (CC BY 4.0)
Except where otherwise noted, this item's licence is described as Attribution 4.0 International (CC BY 4.0)