8TF3

Wildtype rabbit TRPV5 into nanodiscs in complex with econazole

8TF3 の概要

• エントリーDOI: 10.2210/pdb8tf3/pdb
• EMDBエントリー: 41218
• 分子名称: Transient receptor potential cation channel subfamily V member 5, ERGOSTEROL, 1-PALMITOYL-2-LINOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE, ... (4 entities in total)
• 機能のキーワード: trpv5, trp channel, econazole, membrane protein
• 由来する生物種: Oryctolagus cuniculus (rabbit)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 345902.74

構造登録者

De Jesus-Perez, J.J.,Fluck, E.C.,Moiseenkova-Bell, V.Y. (登録日: 2023-07-07, 公開日: 2024-01-10, 最終更新日: 2024-02-14)

主引用文献

De Jesus-Perez, J.J.,Gabrielle, M.,Raheem, S.,Fluck, E.C.,Rohacs, T.,Moiseenkova-Bell, V.Y.
Structural mechanism of TRPV5 inhibition by econazole.
Structure, 32:148-156.e5, 2024

PubMed Abstract: The calcium-selective TRPV5 channel activated by phosphatidylinositol 4,5-bisphosphate [PI(4,5)P] is involved in calcium homeostasis. Recently, cryoelectron microscopy (cryo-EM) provided molecular details of TRPV5 modulation by exogenous and endogenous molecules. However, the details of TRPV5 inhibition by the antifungal agent econazole (ECN) remain elusive due to the low resolution of the currently available structure. In this study, we employ cryo-EM to comprehensively examine how the ECN inhibits TRPV5. By combining our structural findings with site-directed mutagenesis, calcium measurements, electrophysiology, and molecular dynamics simulations, we determined that residues F472 and L475 on the S4 helix, along with residue W495 on the S5 helix, collectively constitute the ECN-binding site. Additionally, the structure of TRPV5 in the presence of ECN and PI(4,5)P, which does not show the bound activator, reveals a potential inhibition mechanism in which ECN competes with PI(4,5)P, preventing the latter from binding, and ultimately pore closure.

PubMed: 38141613
DOI: 10.1016/j.str.2023.11.012

実験手法

ELECTRON MICROSCOPY (2.94 Å)