Structure of an Agonist-Bound Human A2A Adenosine Receptor

• Published in: Science (American Association for the Advancement of Science) Vol. 332; no. 6027; pp. 322 - 327
• Main Authors: FEI XU, HUIXIAN WU, KATRITCH, Vsevolod, GYE WON HAN, JACOBSON, Kenneth A, GAO, Zhan-Guo, CHEREZOV, Vadim, STEVENS, Raymond C
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 15.04.2011; The American Association for the Advancement of Science
• Subjects: Adenosine - analogs & derivatives; Adenosine - chemistry; Adenosine - metabolism; Adenosine A2 Receptor Agonists - chemistry; Adenosine A2 Receptor Agonists - metabolism; Adenosines; agonists; Binding Sites; Biological and medical sciences; Cell physiology; Cellular biology; Crystal structure; Crystalline structure; Crystallography, X-Ray; Displays; Fundamental and applied biological sciences. Psychology; Humans; Hydrogen Bonding; Ligands; Models, Molecular; Molecular and cellular biology; Molecular biology; Molecular biophysics; Movement; opsin; Opsins - chemistry; Opsins - metabolism; Protein Conformation; Protein Structure, Secondary; Proteins; purinergic receptors; Receptor, Adenosine A2A - chemistry; Receptor, Adenosine A2A - metabolism; Receptors; Rhodopsin - chemistry; Rhodopsin - metabolism; Signal transduction; Structure in molecular biology; Surface chemistry; surface proteins; Tilt; Triazines - chemistry; Triazines - metabolism; Triazoles - chemistry; Triazoles - metabolism; Shift; Human; Signal transduction; Agonist; Regulation(control); G protein coupled receptor; Activation; Antagonist; Cell surface; Biological receptor; Crystalline structure
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.1202793

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.