Structure of the full-length glucagon class B G-protein-coupled receptor.
Structure of the full-length glucagon class B G-protein-coupled receptor.
复制标题
全长胰高血糖素 B 类 G 蛋白偶联受体的结构
DOI：
10.1038/nature22363
复制
发表时间：
2017-06-08
期刊：
影响因子：
64.8
通讯作者：
Wu B
中科院分区：
文献类型：
--
作者：
Zhang H;Qiao A;Yang D;Yang L;Dai A;de Graaf C;Reedtz-Runge S;Dharmarajan V;Zhang H;Han GW;Grant TD;Sierra RG;Weierstall U;Nelson G;Liu W;Wu Y;Ma L;Cai X;Lin G;Wu X;Geng Z;Dong Y;Song G;Griffin PR;Lau J;Cherezov V;Yang H;Hanson MA;Stevens RC;Zhao Q;Jiang H;Wang MW;Wu B
人胰高血糖素受体（GCGR）属于B类G蛋白偶联受体（GPCR）家族，在葡萄糖稳态及2型糖尿病的病理生理过程中发挥关键作用。在此，我们报告全长GCGR处于非活性构象时分辨率为3.0埃的晶体结构，该结构包含胞外结构域（ECD）和跨膜结构域（TMD）。这两个结构域由一段含12个残基、被称为“柄区”的片段相连，柄区呈β链构象，而非先前解析的GCGR - TMD结构中所见的α螺旋。第一个胞外环（ECL1）呈β发夹构象，并与柄区相互作用形成紧密的β折叠结构。氢/氘交换、二硫键交联及分子动力学研究表明，柄区和ECL1在调节肽配体结合及受体激活方面发挥着关键作用。这些关于全长GCGR结构的见解加深了我们对B类GPCR信号转导机制的理解。
The human glucagon receptor (GCGR) belongs to the class B G protein-coupled receptor (GPCR) family and plays a key role in glucose homeostasis and the pathophysiology of type 2 diabetes. Here we report the 3.0 Å crystal structure of full-length GCGR containing both extracellular domain (ECD) and transmembrane domain (TMD) in an inactive conformation. The two domains are connected by a 12-residue segment termed the ‘stalk’, which adopts a β-strand conformation, instead of forming an α-helix as observed in the previously solved structure of GCGR-TMD. The first extracellular loop (ECL1) exhibits a β-hairpin conformation and interacts with the stalk to form a compact β-sheet structure. Hydrogen/deuterium exchange, disulfide cross-linking and molecular dynamics studies suggest that the stalk and ECL1 play critical roles in modulating peptide ligand binding and receptor activation. These insights into the full-length GCGR structure deepen our understanding about the signaling mechanisms of class B GPCRs.