Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor.
Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor.
复制标题
人葡萄糖依赖性促胰岛素多肽受体激素识别的结构见解
DOI：
10.7554/elife.68719
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发表时间：
2021-07-13
期刊：
影响因子：
7.7
通讯作者：
Wang MW
中科院分区：
文献类型：
--
作者：
Zhao F;Zhang C;Zhou Q;Hang K;Zou X;Chen Y;Wu F;Rao Q;Dai A;Yin W;Shen DD;Zhang Y;Xia T;Stevens RC;Xu HE;Yang D;Zhao L;Wang MW
葡萄糖依赖性促胰岛素多肽（GIP）是一种肽类激素，通过结合和激活其同源受体GIPR发挥重要的代谢功能。作为一个重要的治疗靶点，GIPR已经受到了密集的结构研究没有成功。在这里，我们报告的cryo-EM结构的人GIPR在复杂的GIP和Gs异源三聚体在全球分辨率为2.9毫米。GIP为单股直螺旋结构，其N端插入受体跨膜结构域（TMD），而C端与胞外结构域和胞外环1密切相关。GIPR利用TMD口袋下半部分的保守残基识别GIP同源肽共有的共同片段，而利用TMD口袋上半部分的非保守残基与GIP特异性残基相互作用。这些结果提供了激素识别和GIPR激活的结构框架。
Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone that exerts crucial metabolic functions by binding and activating its cognate receptor, GIPR. As an important therapeutic target, GIPR has been subjected to intensive structural studies without success. Here, we report the cryo-EM structure of the human GIPR in complex with GIP and a Gs heterotrimer at a global resolution of 2.9 Å. GIP adopts a single straight helix with its N terminus dipped into the receptor transmembrane domain (TMD), while the C-terminus is closely associated with the extracellular domain and extracellular loop 1. GIPR employs conserved residues in the lower half of the TMD pocket to recognize the common segments shared by GIP homologous peptides, while uses non-conserved residues in the upper half of the TMD pocket to interact with residues specific for GIP. These results provide a structural framework of hormone recognition and GIPR activation.