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

Journal Article · Thu Jan 14 00:00:00 EST 2010 · Nature

DOI:https://doi.org/10.1038/nature08650· OSTI ID:1002248

Bokoch, Michael P; Zou, Yaozhong; Rasmussen, Søren G.F.; Liu, Corey W; Nygaard, Rie; Rosenbaum, Daniel M; Fung, Juan José; Choi, Hee-Jung; Thian, Foon Sun; Kobilka, Tong Sun; Puglisi, Joseph D; Weis, William I; Pardo, Leonardo; Prosser, R Scott; Mueller, Luciano; Kobilka, Brian K ^[1]

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1. Stanford-MED

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 the dynamic behaviour of GPCRs not addressable by static, inactive-state crystal structures.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1002248
• Journal Information: Nature, Journal Name: Nature Journal Issue: 01, 2010 Vol. 463
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

36 MATERIALS SCIENCE
CONFORMATIONAL CHANGES
CRYSTAL STRUCTURE
DISEASES
FUNCTIONALS
GTP-ASES
HORMONES
PROTEINS
REGULATIONS
SPECTROSCOPY
SYMPATHOMIMETICS
TARGETS