Journal
SCIENCE
Volume 332, Issue 6027, Pages 322-327Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1202793
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases
- NIH Roadmap Initiative [P50 GM073197]
- NIH [GM075915]
- NSF [IIS0308078]
- Science Foundation Ireland [02-IN1-B266]
- National Cancer Institute [Y1-CO-1020]
- National Institute of General Medical Sciences [Y1-GM-1104]
- [U54 GM094618]
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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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