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Science 332 (6027): 322-327

Copyright © 2011 by the American Association for the Advancement of Science

Structure of an Agonist-Bound Human A2A Adenosine Receptor

Fei Xu,1 Huixian Wu,1 Vsevolod Katritch,2 Gye Won Han,1 Kenneth A. Jacobson,3 Zhan-Guo Gao,3 Vadim Cherezov,1 Raymond C. Stevens1,*

Abstract: Activation of G protein–coupled receptors upon agonist binding is a critical step in the signaling cascade for this family of cell surface proteins. We report the crystal structure of the A2A adenosine receptor (A2AAR) bound to an agonist UK-432097 at 2.7 angstrom resolution. Relative to inactive, antagonist-bound A2AAR, the agonist-bound structure displays an outward tilt and rotation of the cytoplasmic half of helix VI, a movement of helix V, and an axial shift of helix III, resembling the changes associated with the active-state opsin structure. Additionally, a seesaw movement of helix VII and a shift of extracellular loop 3 are likely specific to A2AAR and its ligand. The results define the molecule UK-432097 as a "conformationally selective agonist" capable of receptor stabilization in a specific active-state configuration.

1 Department of Molecular Biology, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
2 Skaggs School of Pharmacy and Pharmaceutical Sciences and San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA 92093, USA.
3 Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA.

* To whom correspondence should be addressed. E-mail: stevens{at}scripps.edu

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