期刊
NATURE
卷 454, 期 7203, 页码 486-491出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature07101
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资金
- Medical Research Council [MC_U105184325, U.1051.04.020(78937), MC_U105178937, MC_U105184322] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
- MRC [MC_U105178937, MC_U105184322, MC_U105184325] Funding Source: UKRI
- Medical Research Council [MC_U105184325, MC_U105184322, MC_U105178937] Funding Source: researchfish
G-protein-coupled receptors have a major role in transmembrane signalling in most eukaryotes and many are important drug targets. Here we report the 2.7 angstrom resolution crystal structure of a beta(1)-adrenergic receptor in complex with the high-affinity antagonist cyanopindolol. The modified turkey (Meleagris gallopavo) receptor was selected to be in its antagonist conformation and its thermostability improved by earlier limited mutagenesis. The ligand-binding pocket comprises 15 side chains from amino acid residues in 4 transmembrane alpha-helices and extracellular loop 2. This loop defines the entrance of the ligand-binding pocket and is stabilized by two disulphide bonds and a sodium ion. Binding of cyanopindolol to the beta(1)-adrenergic receptor and binding of carazolol to the beta(2)-adrenergic receptor involve similar interactions. A short well-defined helix in cytoplasmic loop 2, not observed in either rhodopsin or the beta(2)-adrenergic receptor, directly interacts by means of a tyrosine with the highly conserved DRY motif at the end of helix 3 that is essential for receptor activation.
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