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Science 337 (6091): 232-236

Copyright © 2012 by the American Association for the Advancement of Science

Structural Basis for Allosteric Regulation of GPCRs by Sodium Ions

Wei Liu,1,* Eugene Chun,1,* Aaron A. Thompson,1,* Pavel Chubukov,1 Fei Xu,1 Vsevolod Katritch,1 Gye Won Han,1 Christopher B. Roth,2 Laura H. Heitman,3 Adriaan P. IJzerman,3 Vadim Cherezov,1,{dagger} Raymond C. Stevens1,{dagger}

Abstract: Pharmacological responses of G protein–coupled receptors (GPCRs) can be fine-tuned by allosteric modulators. Structural studies of such effects have been limited due to the medium resolution of GPCR structures. We reengineered the human A2A adenosine receptor by replacing its third intracellular loop with apocytochrome b562RIL and solved the structure at 1.8 angstrom resolution. The high-resolution structure allowed us to identify 57 ordered water molecules inside the receptor comprising three major clusters. The central cluster harbors a putative sodium ion bound to the highly conserved aspartate residue Asp2.50. Additionally, two cholesterols stabilize the conformation of helix VI, and one of 23 ordered lipids intercalates inside the ligand-binding pocket. These high-resolution details shed light on the potential role of structured water molecules, sodium ions, and lipids/cholesterol in GPCR stabilization and function.

1 Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
2 Receptos, San Diego, CA 92121, USA.
3 Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Post Office Box 9502, 2300RA Leiden, Netherlands.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: vcherezo{at}scripps.edu (V.C.); stevens{at}scripps.edu (R.C.S.)

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