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

Michael P. Bokoch, Yaozhong Zou, Søren G. F. Rasmussen, Corey W. Liu, Rie Nygaard, Daniel M. Rosenbaum, Juan José Fung, Hee-Jung Choi, Foon Sun Thian, Tong Sun Kobilka, Joseph D. Puglisi, William I. Weis, Leonardo Pardo, R. Scott Prosser, Luciano Mueller and Brian K. Kobilka ()
Additional contact information
Michael P. Bokoch: Department of Molecular and Cellular Physiology,
Yaozhong Zou: Department of Molecular and Cellular Physiology,
Søren G. F. Rasmussen: Department of Molecular and Cellular Physiology,
Corey W. Liu: Stanford Magnetic Resonance Laboratory, and,
Rie Nygaard: Department of Molecular and Cellular Physiology,
Daniel M. Rosenbaum: Department of Molecular and Cellular Physiology,
Juan José Fung: Department of Molecular and Cellular Physiology,
Hee-Jung Choi: Department of Molecular and Cellular Physiology,
Foon Sun Thian: Department of Molecular and Cellular Physiology,
Tong Sun Kobilka: Department of Molecular and Cellular Physiology,
Joseph D. Puglisi: Stanford Magnetic Resonance Laboratory, and,
William I. Weis: Department of Molecular and Cellular Physiology,
Leonardo Pardo: Laboratori de Medicina Computacional, Unitat de Bioestadística, Universitat Autònoma de Barcelona
R. Scott Prosser: University of Toronto, UTM, Mississauga, Ontario, Canada L5L 1C6
Luciano Mueller: Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA
Brian K. Kobilka: Department of Molecular and Cellular Physiology,

Nature, 2010, vol. 463, issue 7277, 108-112

Abstract: Ligand-specific changes in GPCRs G-protein-coupled receptors (GPCRs) mediate the majority of cellular responses to hormones and neurotransmitters, and these membrane proteins are the largest group of therapeutic targets for a broad range of diseases. It is very difficult to obtain high-resolution X-ray crystal structures of GPCRs; little is known about the functional role(s) of the extracellular surface in receptor activation or about the conformational coupling of the extracellular surface to the native ligand-binding pocket. In this study, Bokoch et al. used NMR spectroscopy to investigate ligand-specific conformational changes around a salt bridge linking extracellular loops 2 and 3 of the β2 adrenergic receptor. They found that drugs that bind within the transmembrane core (and exhibit different efficacies towards G-protein activation) stabilize distinct conformations of the extracellular surface. New therapeutic agents that target this diverse surface could function as allosteric modulators with high subtype selectivity.

Date: 2010
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DOI: 10.1038/nature08650

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