High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor

被引:2666
作者
Cherezov, Vadim
Rosenbaum, Daniel M.
Hanson, Michael A.
Rasmussen, Soren G. F.
Thian, Foon Sun
Kobilka, Tong Sun
Choi, Hee-Jung
Kuhn, Peter
Weis, William I.
Kobilka, Brian K.
Stevens, Raymond C. [1 ]
机构
[1] Stanford Univ, Sch Med, Dept Cellular & Mol Physiol, Stanford, CA 94305 USA
[2] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA
[3] Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA
[4] Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA
关键词
D O I
10.1126/science.1150577
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors constitute the largest family of eukaryotic signal transduction proteins that communicate across the membrane. We report the crystal structure of a human beta(2)-adrenergic receptor-T4 lysozyme fusion protein bound to the partial inverse agonist carazolol at 2.4 angstrom resolution. The structure provides a high-resolution view of a human G protein-coupled receptor bound to a diffusible ligand. Ligand-binding site accessibility is enabled by the second extracellular loop, which is held out of the binding cavity by a pair of closely spaced disulfide bridges and a short helical segment within the loop. Cholesterol, a necessary component for crystallization, mediates an intriguing parallel association of receptor molecules in the crystal lattice. Although the location of carazolol in the beta(2)-adrenergic receptor is very similar to that of retinal in rhodopsin, structural differences in the ligand-binding site and other regions highlight the challenges in using rhodopsin as a template model for this large receptor family.
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页码:1258 / 1265
页数:8
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