7E5E

Crystal structure of GDP-bound GNAS in complex with the cyclic peptide inhibitor GD20

7E5E の概要

• エントリーDOI: 10.2210/pdb7e5e/pdb
• 関連するPDBエントリー: 7BPH
• 分子名称: Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, GD20, GUANOSINE-5'-DIPHOSPHATE, ... (5 entities in total)
• 機能のキーワード: g protein, gnas, adenylyl cyclase, inactive state, inhibitor, mrna display, rapid, cyclic peptide, gd20, signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 171382.83

構造登録者

Hu, Q.,Dai, S.,Shokat, K.M. (登録日: 2021-02-18, 公開日: 2022-03-02, 最終更新日: 2024-10-30)

主引用文献

Dai, S.A.,Hu, Q.,Gao, R.,Blythe, E.E.,Touhara, K.K.,Peacock, H.,Zhang, Z.,von Zastrow, M.,Suga, H.,Shokat, K.M.
State-selective modulation of heterotrimeric G alpha s signaling with macrocyclic peptides.
Cell, 185:3950-, 2022

PubMed Abstract: The G protein-coupled receptor cascade leading to production of the second messenger cAMP is replete with pharmacologically targetable proteins, with the exception of the Gα subunit, Gαs. GTPases remain largely undruggable given the difficulty of displacing high-affinity guanine nucleotides and the lack of other drug binding sites. We explored a chemical library of 10 cyclic peptides to expand the chemical search for inhibitors of this enzyme class. We identified two macrocyclic peptides, GN13 and GD20, that antagonize the active and inactive states of Gαs, respectively. Both macrocyclic peptides fine-tune Gαs activity with high nucleotide-binding-state selectivity and G protein class-specificity. Co-crystal structures reveal that GN13 and GD20 distinguish the conformational differences within the switch II/α3 pocket. Cell-permeable analogs of GN13 and GD20 modulate Gαs/Gβγ signaling in cells through binding to crystallographically defined pockets. The discovery of cyclic peptide inhibitors targeting Gαs provides a path for further development of state-dependent GTPase inhibitors.

PubMed: 36170854
DOI: 10.1016/j.cell.2022.09.019

実験手法

X-RAY DIFFRACTION (1.95 Å)