Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor.
Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor.
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人胰高血糖素样肽 1 受体前变构调节的分子见解
DOI：
10.1038/s41467-021-24058-z
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发表时间：
2021-06-18
影响因子：
16.6
通讯作者：
Wang MW
中科院分区：
文献类型：
--
作者：
Cong Z;Chen LN;Ma H;Zhou Q;Zou X;Ye C;Dai A;Liu Q;Huang W;Sun X;Wang X;Xu P;Zhao L;Xia T;Zhong W;Yang D;Eric Xu H;Zhang Y;Wang MW
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 Gs. 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.
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DOI：
10.1016/bs.apha.2019.04.002
发表时间：
2019-01-01
期刊：
NEUROPSYCHOTHERAPEUTICS
影响因子：
--
作者：
Felder, Christian C.
通讯作者：
Felder, Christian C.
影响因子：
3.6
作者：
Koole, Cassandra;Wootten, Denise;Sexton, Patrick M.
通讯作者：
Sexton, Patrick M.
影响因子：
64.8
作者：
Jazayeri, Ali;Rappas, Mathieu;Marshall, Fiona H.
通讯作者：
Marshall, Fiona H.
影响因子：
5.5
作者：
Hess, Berk
通讯作者：
Hess, Berk
影响因子：
64.8
作者：
Kang Y;Kuybeda O;de Waal PW;Mukherjee S;Van Eps N;Dutka P;Zhou XE;Bartesaghi A;Erramilli S;Morizumi T;Gu X;Yin Y;Liu P;Jiang Y;Meng X;Zhao G;Melcher K;Ernst OP;Kossiakoff AA;Subramaniam S;Xu HE
通讯作者：
Xu HE