7E14

Compound2_GLP-1R_OWL833_Gs complex structure

7E14 の概要

• エントリーDOI: 10.2210/pdb7e14/pdb
• EMDBエントリー: 30936
• 分子名称: Gs, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, G protein, ... (8 entities in total)
• 機能のキーワード: ago-allosteric modulation of glp-1r, membrane protein
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 142599.17

構造登録者

Cong, Z.T.,Chen, L.N.,Ma, H.L.,Yang, D.H.,Xu, H.E.,Zhang, Y.,Wang, M.W. (登録日: 2021-01-30, 公開日: 2021-07-07, 最終更新日: 2024-03-27)

主引用文献

Cong, Z.,Chen, L.N.,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, M.W.
Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor.
Nat Commun, 12:3763-3763, 2021

PubMed Abstract: 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.

PubMed: 34145245
DOI: 10.1038/s41467-021-24058-z

実験手法

ELECTRON MICROSCOPY (2.9 Å)