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PMID: 21393508 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Structure of an agonist-bound human A2A adenosine receptor.

Science (New York, N.Y.) ·Vol. 332 ·No. 6027 ·2011-04-15 ·Pages 322-7

Xu F, Wu H, Katritch V, Han GW, Jacobson KA, Gao ZG, Cherezov V, Stevens RC

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.

MeSH Terms
Adenosine/analogs & derivatives,chemistry,metabolism Adenosine A2 Receptor Agonists/chemistry,metabolism Binding Sites Crystallography, X-Ray Humans Hydrogen Bonding Ligands Models, Molecular Opsins/chemistry,metabolism Protein Conformation Protein Structure, Secondary Receptor, Adenosine A2A/chemistry,metabolism Rhodopsin/chemistry,metabolism Triazines/chemistry,metabolism Triazoles/chemistry,metabolism
Chemicals
Adenosine A2 Receptor Agonists Ligands Opsins Receptor, Adenosine A2A Triazines Triazoles UK-432097 ZM 241385 Rhodopsin Adenosine
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Xu Fei
Department of Molecular Biology, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Wu Huixian
Katritch Vsevolod
Han Gye Won
Jacobson Kenneth A
Gao Zhan-Guo
Cherezov Vadim
Stevens Raymond C
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Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.1202793
Published
2011-04-15
Epub
2011-00-10
Pages
322-7
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC3086811
Subset
IM
Grants
NIGMS NIH HHS · U54 GM094618 · United States
NIGMS NIH HHS · P50 GM073197 · United States
NIGMS NIH HHS · GM075915 · United States
NIGMS NIH HHS · U54 GM094618-01 · United States
NIGMS NIH HHS · R01 GM075915 · United States
NIGMS NIH HHS · Y1-GM-1104 · United States
Intramural NIH HHS · United States
NIGMS NIH HHS · R01 GM089857 · United States
NCI NIH HHS · Y1-CO-1020 · United States
Databases
PDB
3QAK
External Links
PubMed source DOI: 10.1126/science.1202793 PMC Full Text View journal details
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