Structure and function of an irreversible agonist-β2 adrenoceptor complex

Daniel M. Rosenbaum, Cheng Zhang, Joseph A. Lyons, Ralph Holl, David Aragao, Daniel H. Arlow, Søren G. F. Rasmussen, Hee-Jung Choi, Brian T. DeVree, Roger K. Sunahara, Pil Seok Chae, Samuel H. Gellman, Ron O. Dror, David E. Shaw, William I. Weis, Martin Caffrey (), Peter Gmeiner () and Brian K. Kobilka ()
Additional contact information
Daniel M. Rosenbaum: Stanford University School of Medicine, 279 Campus Drive
Cheng Zhang: Stanford University School of Medicine, 279 Campus Drive
Joseph A. Lyons: University of Limerick
Ralph Holl: Friedrich Alexander University, Schuhstrasse 19, 91052 Erlangan, Germany
David Aragao: Membrane Structural and Functional Biology Group, School of Biochemistry and Immunology, Trinity College
Daniel H. Arlow: D. E. Shaw Research
Søren G. F. Rasmussen: Stanford University School of Medicine, 279 Campus Drive
Hee-Jung Choi: Stanford University School of Medicine, 279 Campus Drive
Brian T. DeVree: University of Michigan Medical School
Roger K. Sunahara: University of Michigan Medical School
Pil Seok Chae: University of Wisconsin
Samuel H. Gellman: University of Wisconsin
Ron O. Dror: D. E. Shaw Research
David E. Shaw: D. E. Shaw Research
William I. Weis: Stanford University School of Medicine, 279 Campus Drive
Martin Caffrey: Membrane Structural and Functional Biology Group, School of Biochemistry and Immunology, Trinity College
Peter Gmeiner: Friedrich Alexander University, Schuhstrasse 19, 91052 Erlangan, Germany
Brian K. Kobilka: Stanford University School of Medicine, 279 Campus Drive

Nature, 2011, vol. 469, issue 7329, 236-240

Abstract: β-adrenergic receptor structures Two papers by Brian Kobilka and colleagues describe the X-ray crystal structure of the human β2 adrenergic receptor (β2AR) bound to various agonists. β2AR is a member of the G protein coupled receptor (GPCR) family of membrane-spanning receptors that sense molecules outside the cell and activate internal signalling pathways. With a ubiquitous role in human physiology, GPCRs are prime targets for drug discovery. A third paper by Christopher Tate and his team describes crystal structures of a similar GPCR, the turkey β1-adrenergic receptor (β1AR), bound to full and partial agonists. Together, these new structures reveal the subtle structural changes that accompany agonist binding, showing how binding events inside and outside the cell membrane stabilize the receptor's active state. Agonist binding to β1AR is shown to induce a contraction of the catecholamine-binding pocket relative to the antagonist-bound receptor, and molecular-dynamics simulations of the β2AR agonist complex suggest that the agonist-bound active state spontaneously relaxes to an inactive-like state in the absence of a G protein.

Date: 2011
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DOI: 10.1038/nature09665

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