8FOB

Cryo-EM structure of human TRPV6 in the open state

8FOB の概要

• エントリーDOI: 10.2210/pdb8fob/pdb
• 関連するPDBエントリー: 8FOA
• EMDBエントリー: 29343 29344
• 分子名称: Transient receptor potential cation channel subfamily V member 6, CHOLESTEROL HEMISUCCINATE, 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE, ... (6 entities in total)
• 機能のキーワード: transient receptor potential v family member 6, trp, human, channel, apo state, open, trpv6, trp channels, cancer, oncochannel, 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: 363562.79

構造登録者

Neuberger, A.,Yelshanskaya, M.V.,Nadezhdin, K.D.,Sobolevsky, A.I. (登録日: 2022-12-30, 公開日: 2023-05-24, 最終更新日: 2024-06-19)

主引用文献

Neuberger, A.,Trofimov, Y.A.,Yelshanskaya, M.V.,Nadezhdin, K.D.,Krylov, N.A.,Efremov, R.G.,Sobolevsky, A.I.
Structural mechanism of human oncochannel TRPV6 inhibition by the natural phytoestrogen genistein.
Nat Commun, 14:2659-2659, 2023

PubMed Abstract: Calcium-selective oncochannel TRPV6 is the major driver of cell proliferation in human cancers. While significant effort has been invested in the development of synthetic TRPV6 inhibitors, natural channel blockers have been largely neglected. Here we report the structure of human TRPV6 in complex with the plant-derived phytoestrogen genistein, extracted from Styphnolobium japonicum, that was shown to inhibit cell invasion and metastasis in cancer clinical trials. Despite the pharmacological value, the molecular mechanism of TRPV6 inhibition by genistein has remained enigmatic. We use cryo-EM combined with electrophysiology, calcium imaging, mutagenesis, and molecular dynamics simulations to show that genistein binds in the intracellular half of the TRPV6 pore and acts as an ion channel blocker and gating modifier. Genistein binding to the open channel causes pore closure and a two-fold symmetrical conformational rearrangement in the S4-S5 and S6-TRP helix regions. The unprecedented mechanism of TRPV6 inhibition by genistein uncovers new possibilities in structure-based drug design.

PubMed: 37160865
DOI: 10.1038/s41467-023-38352-5

実験手法

ELECTRON MICROSCOPY (2.71 Å)