The structural basis for agonist and partial agonist action on a β1-adrenergic receptor

Tony Warne, Rouslan Moukhametzianov, Jillian G. Baker, Rony Nehmé, Patricia C. Edwards, Andrew G. W. Leslie, Gebhard F. X. Schertler () and Christopher G. Tate ()
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Tony Warne: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK
Rouslan Moukhametzianov: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK
Jillian G. Baker: Institute of Cell Signalling, C Floor Medical School, Queen’s Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK
Rony Nehmé: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK
Patricia C. Edwards: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK
Andrew G. W. Leslie: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK
Gebhard F. X. Schertler: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK
Christopher G. Tate: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK

Nature, 2011, vol. 469, issue 7329, 241-244

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/nature09746

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