Structural basis for allosteric regulation of GPCRS by sodium ions

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

Research output: Contribution to journalArticle

541 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)232-236
Number of pages5
JournalScience
Volume337
Issue number6091
DOIs
StatePublished - Jul 13 2012
Externally publishedYes

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Allosteric Regulation
G-Protein-Coupled Receptors
Sodium
Ions
Cholesterol
Adenosine A2A Receptors
Lipids
Water
Aspartic Acid
Pharmacology
Ligands

ASJC Scopus subject areas

  • General

Cite this

Liu, W., Chun, E., Thompson, A. A., Chubukov, P., Xu, F., Katritch, V., ... Stevens, R. C. (2012). Structural basis for allosteric regulation of GPCRS by sodium ions. Science, 337(6091), 232-236. https://doi.org/10.1126/science.1219218

Structural basis for allosteric regulation of GPCRS by sodium ions. / Liu, Wei; Chun, Eugene; Thompson, Aaron A.; Chubukov, Pavel; Xu, Fei; Katritch, Vsevolod; Han, Gye Won; Roth, Christopher B.; Heitman, Laura H.; IJzerman, Adriaan P.; Cherezov, Vadim; Stevens, Raymond C.

In: Science, Vol. 337, No. 6091, 13.07.2012, p. 232-236.

Research output: Contribution to journalArticle

Liu, W, Chun, E, Thompson, AA, Chubukov, P, Xu, F, Katritch, V, Han, GW, Roth, CB, Heitman, LH, IJzerman, AP, Cherezov, V & Stevens, RC 2012, 'Structural basis for allosteric regulation of GPCRS by sodium ions', Science, vol. 337, no. 6091, pp. 232-236. https://doi.org/10.1126/science.1219218
Liu W, Chun E, Thompson AA, Chubukov P, Xu F, Katritch V et al. Structural basis for allosteric regulation of GPCRS by sodium ions. Science. 2012 Jul 13;337(6091):232-236. https://doi.org/10.1126/science.1219218
Liu, Wei ; Chun, Eugene ; Thompson, Aaron A. ; Chubukov, Pavel ; Xu, Fei ; Katritch, Vsevolod ; Han, Gye Won ; Roth, Christopher B. ; Heitman, Laura H. ; IJzerman, Adriaan P. ; Cherezov, Vadim ; Stevens, Raymond C. / Structural basis for allosteric regulation of GPCRS by sodium ions. In: Science. 2012 ; Vol. 337, No. 6091. pp. 232-236.
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