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Science. 2019 May 9. pii: eaau5595. doi: 10.1126/science.aau5595. [Epub ahead of print]

Molecular basis for high-affinity agonist binding in GPCRs.

Author information

1
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
2
Sosei Heptares, Steinmetz Building, Granta Park, Great Abington, Cambridge CB21 6GT, UK.
3
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. cgt@mrc-lmb.cam.ac.uk.

Abstract

G protein-coupled receptors (GPCRs) in the G protein-coupled active state have higher affinity for agonists compared to when they are in the inactive state, but the molecular basis for this is unclear. We have determined four active-state structures of the β1-adrenoceptor (β1AR) bound to conformation-specific nanobodies in the presence of agonists of varying efficacy. Comparison with inactive-state structures of β1AR bound to the identical ligands showed a 24-42% reduction in the volume of the orthosteric binding site. Potential hydrogen bonds were also shorter, and there was up to a 30% increase in the number of atomic contacts between the receptor and ligand. This explains the increase in agonist affinity of GPCRs in the active state for a wide range of structurally distinct agonists.

PMID:
31072904
DOI:
10.1126/science.aau5595

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