High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor
High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor
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DOI：
10.1126/science.1150577
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发表时间：
2007-11-23
期刊：
影响因子：
56.9
通讯作者：
Stevens, Raymond C.
中科院分区：
文献类型：
--
作者：
Cherezov, Vadim;Rosenbaum, Daniel M.;Stevens, Raymond C.
异源三聚体鸟嘌呤核苷酸结合蛋白（G蛋白）偶联受体构成了最大的真核细胞跨膜信号转导蛋白家族。我们报告的晶体结构的人β（2）-肾上腺素能受体T4溶菌酶融合蛋白结合的部分反向激动剂卡拉唑醇在2.4埃分辨率。该结构提供了与可扩散配体结合的人G蛋白偶联受体的高分辨率视图。配体结合位点可及性通过第二胞外环实现，其通过一对紧密间隔的二硫桥和环内的短螺旋片段保持在结合腔之外。胆固醇，结晶的必要组成部分，介导一个有趣的平行关联的受体分子在晶格中。虽然卡拉唑醇在β 2肾上腺素能受体中的位置与视紫红质中的视网膜非常相似，但配体结合位点和其他区域的结构差异突出了使用视紫红质作为这个大受体家族的模板模型的挑战。
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.