9Y2B

Cryo-EM structure of the human TRPM4 channel in complex with EGTA and DAB at 37 degrees Celsius

これはPDB形式変換不可エントリーです。

9Y2B の概要

• エントリーDOI: 10.2210/pdb9y2b/pdb
• EMDBエントリー: 72406
• 分子名称: Transient receptor potential cation channel subfamily M member 4, 4,4'-[(pyridin-2-yl)methylene]diphenol (2 entities in total)
• 機能のキーワード: ion channel, trp channel, 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: 538935.20

構造登録者

Jinhong, H.,Wei, L.,Juan, D. (登録日: 2025-08-31, 公開日: 2026-02-04)

主引用文献

Liu, Y.,Hu, J.,Xue, C.,Huang, W.,Ievleva, S.,Lu, W.,Du, J.,Cao, Z.
Noncanonical calcium-independent TRPM4 activation governs intestinal fluid homeostasis.
Nat Commun, 2026

PubMed Abstract: Imbalance in intestinal fluid homeostasis leads to nutrient malabsorption, intestinal tissue destruction, and systemic inflammation. Transient receptor potential melastatin 4 (TRPM4) is a calcium-activated, non-selective monovalent cation channel converting chemical signals (Ca) into electrical signals (membrane depolarization). Here, we show the TRPM4 channel as a direct target of bisacodyl (BIC), a widely used clinical drug for chronic constipation management, and its active metabolite, deacetyl bisacodyl (DAB). DAB-induced laxative effects are abolished in global and intestinal epithelium-specific TRPM4-knockout mice, establishing the essential role of TRPM4 in intestinal fluid regulation. Furthermore, our structural work reveals DAB bound to an uncharacterized pocket, marking it as a non-Ca TRPM4 agonist and unveiling a noncanonical Ca-independent activation mechanism. Additionally, we delineate a signaling axis, TRPM4 → VGCC/NCX → ANO1, that governs ion homeostasis in the epithelium. Together, these findings establish TRPM4 as a key regulator of intestinal fluid balance and reveal its noncanonical calcium-independent activation as a therapeutic strategy for constipation.

PubMed: 41507162
DOI: 10.1038/s41467-025-68014-7

実験手法

ELECTRON MICROSCOPY (3.2 Å)