New insights into GPCR coupling and dimerisation from cryo-EM structures
- PMID: 36963163
- PMCID: PMC10423944
- DOI: 10.1016/j.sbi.2023.102574
New insights into GPCR coupling and dimerisation from cryo-EM structures
Abstract
Over the past three years (2020-2022) more structures of GPCRs have been determined than in the previous twenty years (2000-2019), primarily of GPCR complexes that are large enough for structure determination by single-particle cryo-EM. This review will present some structural highlights that have advanced our molecular understanding of promiscuous G protein coupling, how a G protein receptor kinase and β-arrestins couple to GPCRs, and GPCR dimerisation. We will also discuss advances in the use of gene fusions, nanobodies, and Fab fragments to facilitate the structure determination of GPCRs in the inactive state that, on their own, are too small for structure determination by single-particle cryo-EM.
Copyright © 2023 MRC Laboratory of Molecular Biology. Published by Elsevier Ltd.. All rights reserved.
Conflict of interest statement
Declaration of competing interest CGT is a shareholder and SAB member of Sosei Heptares. None of the other authors have any conflicts to declare.
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In silico screening of GPCRs using an ultra-large virtual library was shown to be an exceedingly effective tool for finding rapidly novel small molecules that bind to the orthosteric binding site. Very often, these initial hits already bound with nanomolar affinity and required little further diversification to obtain potent ligands.
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