9OLX

Structure of a constitutively open human TRPC3 mutant in the inhibited state

これはPDB形式変換不可エントリーです。

9OLX の概要

• エントリーDOI: 10.2210/pdb9olx/pdb
• EMDBエントリー: 70601
• 分子名称: Short transient receptor potential channel 3, UNKNOWN LIGAND, (3,4-dihydroisoquinolin-2(1H)-yl)[2-(4-methoxyanilino)-1,3-thiazol-4-yl]methanone (3 entities in total)
• 機能のキーワード: trpc3, cerebellar ataxia, moonwalker, 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: 382459.81

構造登録者

Bell, B.,Baker, M.L.,Cordero-Morales, J.F. (登録日: 2025-05-13, 公開日: 2026-03-25, 最終更新日: 2026-04-08)

主引用文献

Bell, B.,Jaramillo-Granada, A.M.,Romero, L.O.,Gutierrez, I.A.,Mallampalli, V.K.P.S.,Fan, G.,Varma, S.,Baker, M.L.,Serysheva, I.I.,Vasquez, V.,Cordero-Morales, J.F.
Functional and structural basis of a hypermorphic TRPC3 variant.
Sci Adv, 12:eaec9284-eaec9284, 2026

PubMed Abstract: Cerebellar ataxias are characterized by impaired motor coordination resulting from neuronal dysfunction within the cerebellum. The mechanisms underlying this pathology and its cerebellar-specific neurodegeneration remain unknown. We uncover how a gain-of-function canonical transient receptor potential member 3 (TRPC3) mutation, coupled with a cerebellum-specific isoform, stabilizes the channel's open state, resists the leading inhibitor Pyr3, and drives calcium-dependent cell death. Restoring calcium homeostasis by expressing a Purkinje cell calcium pump improves cell viability. Transgenic expression of the TRPC3 hypermorphic variant in induces neurodegeneration, confirming its pathogenicity across species. Cryo-electron microscopy and molecular simulations reveal the structural basis for the stabilization of the cerebellar-specific TRPC3 variant in its open state and uncover a druggable allosteric inhibitory binding site. These findings provide an explanation for the vulnerability of cerebellar neurons in TRPC3-associated ataxias and highlight a site for therapeutic intervention.

PubMed: 41880503
DOI: 10.1126/sciadv.aec9284

実験手法

ELECTRON MICROSCOPY (3.3 Å)