9EKS

ML2-SA1 bound TRPML1-V432A/A433G in a partially open state

これはPDB形式変換不可エントリーです。

9EKS の概要

• エントリーDOI: 10.2210/pdb9eks/pdb
• EMDBエントリー: 48135
• 分子名称: Mucolipin-1, (3aS,4S,7R,7aS)-3-(2,6-dichlorophenyl)-3a,4,5,6,7,7a-hexahydro-4,7-methano-1,2-benzoxazole (2 entities in total)
• 機能のキーワード: trpml, calcium channel, ion transport, cryo-em, transport 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: 265288.19

構造登録者

Schmiege, P.,Li, X. (登録日: 2024-12-03, 公開日: 2025-06-18, 最終更新日: 2026-01-07)

主引用文献

Schmiege, P.,Jaslan, D.,Fine, M.,Sadanandan, N.P.,Hatton, A.,Elghobashi-Meinhardt, N.,Grimm, C.,Li, X.
TRPML2 in distinct states reveals the activation and modulation principles of the TRPML family.
Nat Commun, 16:5325-5325, 2025

PubMed Abstract: TRPML2 activity is critical for endolysosomal integrity and chemokine secretion, and can be modulated by various ligands. Interestingly, two ML-SI3 isomers regulate TRPML2 oppositely. The molecular mechanism underlying this unique isomeric preference as well as the TRPML2 agonistic mechanism remains unknown. Here, we present six cryo-EM structures of human TRPML2 in distinct states revealing that the π-bulge of the S6 undergoes a π-α transition upon agonist binding, highlighting the remarkable role of the π-bulge in ion channel regulation. Moreover, we identify that PI(3,5)P allosterically affects the pose of ML2-SA1, a TRPML2 specific activator, resulting in an open channel without the π-α transition. Functional and structural studies show that mutating the S5 of TRPML1 to that of TRPML2 enables the mutated TRPML1 to be activated by (+)ML-SI3 and ML2-SA1. Thus, our work elucidates the activation mechanism of TRPML channels and paves the way for the development of selective TRPML modulators.

PubMed: 40527873
DOI: 10.1038/s41467-025-60710-8

実験手法

ELECTRON MICROSCOPY (2.42 Å)