8JU6

Structure of human TRPV4 with antagonist GSK279

8JU6 の概要

• エントリーDOI: 10.2210/pdb8ju6/pdb
• EMDBエントリー: 36660
• 分子名称: Transient receptor potential cation channel subfamily V member 4,3C-GFP, 1-({(5S,7S)-3-[5-(2-hydroxypropan-2-yl)pyrazin-2-yl]-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl}methyl)-1H-benzimidazole-6-carbonitrile (2 entities in total)
• 機能のキーワード: channel, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 516356.30

構造登録者

Fan, J.,Lei, X. (登録日: 2023-06-24, 公開日: 2024-05-08, 最終更新日: 2025-07-23)

主引用文献

Fan, J.,Guo, C.,Liao, D.,Ke, H.,Lei, J.,Xie, W.,Tang, Y.,Tominaga, M.,Huang, Z.,Lei, X.
Structural Pharmacology of TRPV4 Antagonists.
Adv Sci, 11:e2401583-e2401583, 2024

PubMed Abstract: The nonselective calcium-permeable Transient Receptor Potential Cation Channel Subfamily V Member4 (TRPV4) channel regulates various physiological activities. Dysfunction of TRPV4 is linked to many severe diseases, including edema, pain, gastrointestinal disorders, lung diseases, and inherited neurodegeneration. Emerging TRPV4 antagonists show potential clinical benefits. However, the molecular mechanisms of TRPV4 antagonism remain poorly understood. Here, cryo-electron microscopy (cryo-EM) structures of human TRPV4 are presented in-complex with two potent antagonists, revealing the detailed binding pockets and regulatory mechanisms of TRPV4 gating. Both antagonists bind to the voltage-sensing-like domain (VSLD) and stabilize the channel in closed states. These two antagonists induce TRPV4 to undergo an apparent fourfold to twofold symmetry transition. Moreover, it is demonstrated that one of the antagonists binds to the VSLD extended pocket, which differs from the canonical VSLD pocket. Complemented with functional and molecular dynamics simulation results, this study provides crucial mechanistic insights into TRPV4 regulation by small-molecule antagonists, which may facilitate future drug discovery targeting TRPV4.

PubMed: 38659239
DOI: 10.1002/advs.202401583

実験手法

ELECTRON MICROSCOPY (3.45 Å)