Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

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.)


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
A Two-state Model for the Diffusion of the A2A Adenosine Receptor in Hippocampal Neurons: AGONIST-INDUCED SWITCH TO SLOW MOBILITY IS MODIFIED BY SYNAPSE-ASSOCIATED PROTEIN 102 (SAP102).
P. Thurner, I. Gsandtner, O. Kudlacek, D. Choquet, C. Nanoff, M. Freissmuth, and J. Zezula (2014)
J. Biol. Chem. 289, 9263-9274
   Abstract »    Full Text »    PDF »
The Second Extracellular Loop of the Adenosine A1 Receptor Mediates Activity of Allosteric Enhancers.
D. P. Kennedy, F. M. McRobb, S. A. Leonhardt, M. Purdy, H. Figler, M. A. Marshall, M. Chordia, R. Figler, J. Linden, R. Abagyan, et al. (2014)
Mol. Pharmacol. 85, 301-309
   Abstract »    Full Text »    PDF »
Do Plants Contain G Protein-Coupled Receptors?.
B. Taddese, G. J. G. Upton, G. R. Bailey, S. R. D. Jordan, N. Y. Abdulla, P. J. Reeves, and C. A. Reynolds (2014)
Plant Physiology 164, 287-307
   Abstract »    Full Text »    PDF »
Agonist-dependent Signaling by Group I Metabotropic Glutamate Receptors Is Regulated by Association with Lipid Domains.
R. Kumari, C. Castillo, and A. Francesconi (2013)
J. Biol. Chem. 288, 32004-32019
   Abstract »    Full Text »    PDF »
Mu Opioids and Their Receptors: Evolution of a Concept.
G. W. Pasternak and Y.-X. Pan (2013)
Pharmacol. Rev. 65, 1257-1317
   Abstract »    Full Text »    PDF »
Discovery of positive allosteric modulators and silent allosteric modulators of the {mu}-opioid receptor.
N. T. Burford, M. J. Clark, T. S. Wehrman, S. W. Gerritz, M. Banks, J. O'Connell, J. R. Traynor, and A. Alt (2013)
PNAS 110, 10830-10835
   Abstract »    Full Text »    PDF »
Of receptors, channels, and watching the red cell center lose hold.
E. M. Adler (2012)
J. Gen. Physiol. 140, 243-244
   Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882