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Science. 2019 May 24;364(6442):775-778. doi: 10.1126/science.aau5595. Epub 2019 May 9.

Molecular basis for high-affinity agonist binding in GPCRs.

Author information

1
Medical Research Council (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
Medical Research Council (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 as compared with 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 to 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
PMCID:
PMC6586556
[Available on 2019-11-24]
DOI:
10.1126/science.aau5595

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