7S8C

Cryo-EM structure of human TRPV6 in complex with inhibitor econazole

7S8C の概要

• エントリーDOI: 10.2210/pdb7s8c/pdb
• 関連するPDBエントリー: 7S88 7S89 7S8B
• EMDBエントリー: 24890 24891 24892 24893
• 分子名称: Transient receptor potential cation channel subfamily V member 6, 1-[(2R)-2-[(4-chlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole, CHOLESTEROL HEMISUCCINATE, ... (6 entities in total)
• 機能のキーワード: transient receptor potential v family member 6, trp, channel, econazole, inhibitor, antagonist, cnw11, nanodiscs, trpv6, membrane protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 333289.51

構造登録者

Neuberger, A.,Nadezhdin, K.D.,Sobolevsky, A.I. (登録日: 2021-09-17, 公開日: 2021-11-17, 最終更新日: 2024-06-05)

主引用文献

Neuberger, A.,Nadezhdin, K.D.,Sobolevsky, A.I.
Structural mechanisms of TRPV6 inhibition by ruthenium red and econazole.
Nat Commun, 12:6284-6284, 2021

PubMed Abstract: TRPV6 is a calcium-selective ion channel implicated in epithelial Ca uptake. TRPV6 inhibitors are needed for the treatment of a broad range of diseases associated with disturbed calcium homeostasis, including cancers. Here we combine cryo-EM, calcium imaging, and mutagenesis to explore molecular bases of human TRPV6 inhibition by the antifungal drug econazole and the universal ion channel blocker ruthenium red (RR). Econazole binds to an allosteric site at the channel's periphery, where it replaces a lipid. In contrast, RR inhibits TRPV6 by binding in the middle of the ion channel's selectivity filter and plugging its pore like a bottle cork. Despite different binding site locations, both inhibitors induce similar conformational changes in the channel resulting in closure of the gate formed by S6 helices bundle crossing. The uncovered molecular mechanisms of TRPV6 inhibition can guide the design of a new generation of clinically useful inhibitors.

PubMed: 34725357
DOI: 10.1038/s41467-021-26608-x

実験手法

ELECTRON MICROSCOPY (2.85 Å)