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dc.contributor.authorSolt, Andras S
dc.contributor.authorBostock, Mark J
dc.contributor.authorShrestha, Binesh
dc.contributor.authorKumar, Prashant
dc.contributor.authorWarne, Tony
dc.contributor.authorTate, Christopher G
dc.contributor.authorNietlispach, Daniel
dc.date.accessioned2018-06-08T13:44:33Z
dc.date.available2018-06-08T13:44:33Z
dc.date.issued2017-11-27
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/276794
dc.description.abstractA complex conformational energy landscape determines G-protein-coupled receptor (GPCR) signalling via intracellular binding partners (IBPs), e.g., Gs and β-arrestin. Using 13C methyl methionine NMR for the β1-adrenergic receptor, we identify ligand efficacy-dependent equilibria between an inactive and pre-active state and, in complex with Gs-mimetic nanobody, between more and less active ternary complexes. Formation of a basal activity complex through ligand-free nanobody-receptor interaction reveals structural differences on the cytoplasmic receptor side compared to the full agonist-bound nanobody-coupled form, suggesting that ligand-induced variations in G-protein interaction underpin partial agonism. Significant differences in receptor dynamics are observed ranging from rigid nanobody-coupled states to extensive μs-to-ms timescale dynamics when bound to a full agonist. We suggest that the mobility of the full agonist-bound form primes the GPCR to couple to IBPs. On formation of the ternary complex, ligand efficacy determines the quality of the interaction between the rigidified receptor and an IBP and consequently the signalling level.
dc.format.mediumElectronic
dc.languageeng
dc.language.isoen
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectAnimals
dc.subjectSpodoptera
dc.subjectGTP-Binding Protein alpha Subunits, Gs
dc.subjectReceptors, Adrenergic, beta-2
dc.subjectLigands
dc.subjectCrystallography, X-Ray
dc.subjectNuclear Magnetic Resonance, Biomolecular
dc.subjectSignal Transduction
dc.subjectProtein Conformation
dc.subjectAdrenergic beta-2 Receptor Agonists
dc.subjectSf9 Cells
dc.subjectSingle-Domain Antibodies
dc.titleInsight into partial agonism by observing multiple equilibria for ligand-bound and Gs-mimetic nanobody-bound β1-adrenergic receptor.
dc.typeArticle
prism.issueIdentifier1
prism.publicationDate2017
prism.publicationNameNat Commun
prism.startingPage1795
prism.volume8
dc.identifier.doi10.17863/CAM.13874
dcterms.dateAccepted2017-11-01
rioxxterms.versionofrecord10.1038/s41467-017-02008-y
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.licenseref.startdate2017-11-27
dc.contributor.orcidBostock, Mark J [0000-0001-6717-5786]
dc.contributor.orcidTate, Christopher G [0000-0002-2008-9183]
dc.contributor.orcidNietlispach, Daniel [0000-0003-4364-9291]
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Review
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/K01983X/1)
pubs.funder-project-idMRC (MR/L014254/1)
pubs.funder-project-idMRC (1509279)
cam.issuedOnline2017-11-27


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