拟肽
化学
兴奋剂
G蛋白偶联受体
痛苦
受体
立体化学
功能选择性
药物发现
体内
药理学
肽
生物化学
医学
生物
政治
生物技术
政治学
法学
作者
Zhaotong Cong,Qingtong Zhou,Yang Li,Li-Nan Chen,Zi-Chen Zhang,Anyi Liang,Qing Liu,Xiaoyan Wu,Antao Dai,Tian Xia,Wei Wu,Yan Zhang,Dehua Yang,Mingwei Wang
标识
DOI:10.1073/pnas.2200155119
摘要
Significance Glucagon-like peptide-1 receptor (GLP-1R) agonists are efficacious in the treatment of type 2 diabetes and obesity. While most clinically used agents require subcutaneous injection, Boc5, as the first orthosteric nonpeptidic agonist of GLP-1R, suffers from poor oral bioavailability that hinders its therapeutic development. The cryoelectron microscopy structures of Boc5 and its closely related analog WB4-24 presented here reveal a binding pocket located deeper in the transmembrane domain for nonpeptidic GLP-1R agonists. Molecular interaction with this site may facilitate a broad spectrum of in vivo agonistic activities, in addition to that with the upper helical bundles presumably responsible for biased signaling. These findings deepen our understanding of peptidomimetic agonism at GLP-1R and may help design better drug leads against this important target.
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