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Molecular basis for high-affinity agonist binding in GPCRs.

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 ?1-adrenoceptor (?1AR) bound to conformation-specific nanobodies in the presence of agonists of varying efficacy. Comparison with inactive-state structures of ?1AR 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.

SUBMITTER: Warne T

PROVIDER: S-EPMC6586556 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Molecular basis for high-affinity agonist binding in GPCRs.

Warne Tony T Edwards Patricia C PC Doré Andrew S AS Leslie Andrew G W AGW Tate Christopher G CG

Science (New York, N.Y.) 20190509 6442

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 2 ...[more]

PMID: 31072904

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