变构调节
肽
G蛋白偶联受体
受体
动力学
兴奋剂
突变
生物物理学
化学
跨膜蛋白
细胞生物学
胰高血糖素样肽-1
生物化学
生物
突变
内分泌学
物理
基因
糖尿病
2型糖尿病
量子力学
作者
Giuseppe Deganutti,Yi-Lynn Liang,Xin Zhang,Maryam Khoshouei,Lachlan Clydesdale,Matthew J. Belousoff,Hari Venugopal,Tin T. Truong,Alisa Glukhova,Andrew N. Keller,Karen J. Gregory,Katie Leach,Arthur Christopoulos,Radostin Danev,Christopher A. Reynolds,Peishen Zhao,Patrick M. Sexton,Denise Wootten
标识
DOI:10.1038/s41467-021-27760-0
摘要
Abstract The glucagon-like peptide-1 receptor (GLP-1R) has broad physiological roles and is a validated target for treatment of metabolic disorders. Despite recent advances in GLP-1R structure elucidation, detailed mechanistic understanding of how different peptides generate profound differences in G protein-mediated signalling is still lacking. Here we combine cryo-electron microscopy, molecular dynamics simulations, receptor mutagenesis and pharmacological assays, to interrogate the mechanism and consequences of GLP-1R binding to four peptide agonists; glucagon-like peptide-1, oxyntomodulin, exendin-4 and exendin-P5. These data reveal that distinctions in peptide N-terminal interactions and dynamics with the GLP-1R transmembrane domain are reciprocally associated with differences in the allosteric coupling to G proteins. In particular, transient interactions with residues at the base of the binding cavity correlate with enhanced kinetics for G protein activation, providing a rationale for differences in G protein-mediated signalling efficacy from distinct agonists.
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