Biochemical and Biophysical Research Communications ( IF 3.1 ) Pub Date : 2020-09-30 , DOI: 10.1016/j.bbrc.2020.08.042 Satoshi Fukuhara , Kazuhiro Kobayashi , Tsukasa Kusakizako , Wataru Iida , Masahiko Kato , Wataru Shihoya , Osamu Nureki
Secretin is a gastrointestinal hormone that exerts multiple physiological functions via activation of the secretin receptor (SECR). SECR belongs to the class B G-protein-coupled receptors and is involved in various processes, such as regulation of the pH of the duodenal content, food intake, and water homeostasis. Here, we report a cryo-electron microscopy structure of human SECR bound to secretin and an engineered Gs heterotrimer. The structure revealed the basic architecture of SECR and the secretin binding mode. A structural comparison of the SECR and PAC1R transmembrane domains revealed that transmembrane helices 1 and 2 play a prominent role in secretin recognition. Moreover, the extracellular domain of SECR is perpendicular to the TMD, unlike that of PAC1R. This comparison revealed the diverged peptide recognition mechanisms of these receptors, which belong to the same subgroup. Our structural information will facilitate drug discovery research for clinical applications.
中文翻译:
人促胰液素受体与工程化异源三聚体G蛋白偶联的结构
促胰液素是一种胃肠激素,通过激活促胰液素受体(SECR)发挥多种生理功能。SECR属于B类G蛋白偶联受体,参与各种过程,例如十二指肠内含物的pH值调节,食物摄入和水体内平衡。在这里,我们报告人SECR绑定到促胰液素和工程Gs异源三聚体的低温电子显微镜结构。该结构揭示了SECR的基本结构和促胰液素结合模式。SECR和PAC1R跨膜结构域的结构比较表明,跨膜螺旋1和2在secretin识别中起着重要作用。此外,与PAC1R不同,SECR的胞外域垂直于TMD。该比较揭示了属于同一亚组的这些受体的不同的肽识别机制。我们的结构信息将有助于临床研究中的药物发现研究。