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Title: Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor

Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor G-protein-coupled receptors (GPCRs) are seven-transmembrane proteins that mediate most cellular responses to hormones and neurotransmitters. They are the largest group of therapeutic targets for a broad spectrum of diseases. Recent crystal structures of GPCRs have revealed structural conservation extending from the orthosteric ligand-binding site in the transmembrane core to the cytoplasmic G-protein-coupling domains. In contrast, the extracellular surface (ECS) of GPCRs is remarkably diverse and is therefore an ideal target for the discovery of subtype-selective drugs. However, little is known about the functional role of the ECS in receptor activation, or about conformational coupling of this surface to the native ligand-binding pocket. Here we use NMR spectroscopy to investigate ligand-specific conformational changes around a central structural feature in the ECS of the {beta}{sub 2} adrenergic receptor: a salt bridge linking extracellular loops 2 and 3. Small-molecule drugs that bind within the transmembrane core and exhibit different efficacies towards G-protein activation (agonist, neutral antagonist and inverse agonist) also stabilize distinct conformations of the ECS. We thereby demonstrate conformational coupling between the ECS and the orthosteric binding site, showing that drugs targeting this diverse surface could function as allosteric modulators with high subtype selectivity. Moreover, these studies provide a new insight into more » the dynamic behaviour of GPCRs not addressable by static, inactive-state crystal structures. « less
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Publication Date:
OSTI Identifier:OSTI ID: 1002248
Resource Type:Journal Article
Resource Relation:Journal Name: Nature; Journal Volume: 463; Journal Issue: 01, 2010
Research Org:Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
Sponsoring Org:USDOE
Country of Publication:United States
Language:ENGLISH
Subject: 36 MATERIALS SCIENCE; CONFORMATIONAL CHANGES; CRYSTAL STRUCTURE; DISEASES; FUNCTIONALS; GTP-ASES; HORMONES; PROTEINS; REGULATIONS; SPECTROSCOPY; SYMPATHOMIMETICS; TARGETS