School of Pharmacy, Fudan University, Shanghai, China.
The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Nat Commun. 2021 Jun 18;12(1):3763. doi: 10.1038/s41467-021-24058-z.
The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric G. The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer insights into the structural basis of ago-allosterism at GLP-1R and may aid the design of better therapeutics.
胰高血糖素样肽-1（GLP-1）受体是代谢紊乱的一种经过验证的药物靶点。变构调节剂既能单独作为激动剂发挥作用，也能增强正构配体的效力。然而，变构作用的分子细节仍然难以捉摸。在这里，我们报告了 GLP-1R 与（i）化合物 2（一种变构调节剂）；（ii）化合物 2 和 GLP-1；以及（iii）化合物 2 和 LY3502970（一种小分子激动剂）结合的三种冷冻电子显微镜结构，均与异三聚体 G 结合。这些结构表明，化合物 2 与 TM6 细胞质末端的 C347 共价结合，并与 ECD 协同触发其向外运动，其 N 端穿透 GLP-1 结合位点。这使得化合物 2 能够通过增强激动剂结合和 G 蛋白偶联来执行正变构调节。我们的发现为 GLP-1R 上的变构作用提供了结构基础方面的见解，并可能有助于设计更好的治疗药物。
