Structural Basis for Allosteric Regulation of GPCRs by Sodium Ions

Overview

Journal Science

Specialty Science

Date 2012 Jul 17

PMID 22798613

Citations 436

Authors

Wei Liu

Eugene Chun

Aaron A Thompson

Pavel Chubukov

Fei Xu

Vsevolod Katritch

Gye Won Han

Christopher B Roth

Laura H Heitman

Adriaan P IJzerman

Vadim Cherezov

Raymond C Stevens

Affiliations

Soon will be listed here.

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 A(2A) adenosine receptor by replacing its third intracellular loop with apocytochrome b(562)RIL 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 Asp(2.50). 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.

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