Structure of an Agonist-bound Human A2A Adenosine Receptor

Overview

Journal Science

Specialty Science

Date 2011 Mar 12

PMID 21393508

Citations 391

Authors

Fei Xu

Huixian Wu

Vsevolod Katritch

Gye Won Han

Kenneth A Jacobson

Zhan-Guo Gao

Vadim Cherezov

Raymond C Stevens

Affiliations

Soon will be listed here.

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 A(2A) adenosine receptor (A(2A)AR) bound to an agonist UK-432097 at 2.7 angstrom resolution. Relative to inactive, antagonist-bound A(2A)AR, 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 A(2A)AR 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.

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References

Rosenbaum D, Zhang C, Lyons J, Holl R, Aragao D, Arlow D . Structure and function of an irreversible agonist-β(2) adrenoceptor complex. Nature. 2011; 469(7329):236-40. PMC: 3074335. DOI: 10.1038/nature09665. View

Ivanov A, Barak D, Jacobson K . Evaluation of homology modeling of G-protein-coupled receptors in light of the A(2A) adenosine receptor crystallographic structure. J Med Chem. 2009; 52(10):3284-92. PMC: 2720635. DOI: 10.1021/jm801533x. View

Jiang Q, Van Rhee A, Kim J, Yehle S, Wess J, Jacobson K . Hydrophilic side chains in the third and seventh transmembrane helical domains of human A2A adenosine receptors are required for ligand recognition. Mol Pharmacol. 1996; 50(3):512-21. PMC: 3418326. View

Vogel R, Siebert F . Conformations of the active and inactive states of opsin. J Biol Chem. 2001; 276(42):38487-93. DOI: 10.1074/jbc.M105423200. View

Jaakola V, Griffith M, Hanson M, Cherezov V, Chien E, Lane J . The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science. 2008; 322(5905):1211-7. PMC: 2586971. DOI: 10.1126/science.1164772. View

Sansuk K, Deupi X, Torrecillas I, Jongejan A, Nijmeijer S, Bakker R . A structural insight into the reorientation of transmembrane domains 3 and 5 during family A G protein-coupled receptor activation. Mol Pharmacol. 2010; 79(2):262-9. DOI: 10.1124/mol.110.066068. View

Katritch V, Reynolds K, Cherezov V, Hanson M, Roth C, Yeager M . Analysis of full and partial agonists binding to beta2-adrenergic receptor suggests a role of transmembrane helix V in agonist-specific conformational changes. J Mol Recognit. 2009; 22(4):307-18. PMC: 2693451. DOI: 10.1002/jmr.949. View

Ahuja S, Smith S . Multiple switches in G protein-coupled receptor activation. Trends Pharmacol Sci. 2009; 30(9):494-502. DOI: 10.1016/j.tips.2009.06.003. View

Fredholm B, IJzerman A, Jacobson K, Linden J, Muller C . International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update. Pharmacol Rev. 2011; 63(1):1-34. PMC: 3061413. DOI: 10.1124/pr.110.003285. View

10.

Katritch V, Kufareva I, Abagyan R . Structure based prediction of subtype-selectivity for adenosine receptor antagonists. Neuropharmacology. 2010; 60(1):108-15. PMC: 2980563. DOI: 10.1016/j.neuropharm.2010.07.009. View

11.

Scheerer P, Park J, Hildebrand P, Kim Y, Krauss N, Choe H . Crystal structure of opsin in its G-protein-interacting conformation. Nature. 2008; 455(7212):497-502. DOI: 10.1038/nature07330. View

12.

Wacker D, Fenalti G, Brown M, Katritch V, Abagyan R, Cherezov V . Conserved binding mode of human beta2 adrenergic receptor inverse agonists and antagonist revealed by X-ray crystallography. J Am Chem Soc. 2010; 132(33):11443-5. PMC: 2923663. DOI: 10.1021/ja105108q. View

13.

Kim J, Wess J, Van Rhee A, Schoneberg T, Jacobson K . Site-directed mutagenesis identifies residues involved in ligand recognition in the human A2a adenosine receptor. J Biol Chem. 1995; 270(23):13987-97. PMC: 3427751. DOI: 10.1074/jbc.270.23.13987. View

14.

Cristalli G, Muller C, Volpini R . Recent developments in adenosine A2A receptor ligands. Handb Exp Pharmacol. 2009; (193):59-98. DOI: 10.1007/978-3-540-89615-9_3. View

15.

Park J, Scheerer P, Hofmann K, Choe H, Ernst O . Crystal structure of the ligand-free G-protein-coupled receptor opsin. Nature. 2008; 454(7201):183-7. DOI: 10.1038/nature07063. View

16.

Tchilibon S, Kim S, Gao Z, Harris B, Blaustein J, Gross A . Exploring distal regions of the A3 adenosine receptor binding site: sterically constrained N6-(2-phenylethyl)adenosine derivatives as potent ligands. Bioorg Med Chem. 2004; 12(9):2021-34. PMC: 4667970. DOI: 10.1016/j.bmc.2004.02.037. View

17.

Gao Z, IJzerman A . Allosteric modulation of A(2A) adenosine receptors by amiloride analogues and sodium ions. Biochem Pharmacol. 2000; 60(5):669-76. DOI: 10.1016/s0006-2952(00)00360-9. View

18.

Wu B, Chien E, Mol C, Fenalti G, Liu W, Katritch V . Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science. 2010; 330(6007):1066-71. PMC: 3074590. DOI: 10.1126/science.1194396. View

19.

Jiang Q, Lee B, Glashofer M, Van Rhee A, Jacobson K . Mutagenesis reveals structure-activity parallels between human A2A adenosine receptors and biogenic amine G protein-coupled receptors. J Med Chem. 1997; 40(16):2588-95. PMC: 3449164. DOI: 10.1021/jm970084v. View

20.

Rasmussen S, Choi H, Rosenbaum D, Kobilka T, Thian F, Edwards P . Crystal structure of the human beta2 adrenergic G-protein-coupled receptor. Nature. 2007; 450(7168):383-7. DOI: 10.1038/nature06325. View