期刊
SCIENCE
卷 322, 期 5905, 页码 1211-1217出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1164772
关键词
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资金
- NIH Roadmap Initiative [P50 GM073197]
- Protein Structure Initiative [U54 GM074961]
- Dutch Top Institute Pharma
- GPCR forum program [D1-105]
- National Institutes of Health [GM075915]
- National Science Foundation [IIS0308078]
- Science Foundation Ireland [02-IN1-B266]
- National Cancer Institute [Y1-CO-1020]
- National Institute of General Medical Sciences [Y1-GM-1104]
The adenosine class of heterotrimeric guanine nucleotide- binding protein ( G protein)- coupled receptors ( GPCRs) mediates the important role of extracellular adenosine in many physiological processes and is antagonized by caffeine. We have determined the crystal structure of the human A(2A) adenosine receptor, in complex with a high- affinity subtype- selective antagonist, ZM241385, to 2.6 angstrom resolution. Four disulfide bridges in the extracellular domain, combined with a subtle repacking of the transmembrane helices relative to the adrenergic and rhodopsin receptor structures, define a pocket distinct from that of other structurally determined GPCRs. The arrangement allows for the binding of the antagonist in an extended conformation, perpendicular to the membrane plane. The binding site highlights an integral role for the extracellular loops, together with the helical core, in ligand recognition by this class of GPCRs and suggests a role for ZM241385 in restricting the movement of a tryptophan residue important in the activation mechanism of the class A receptors.
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