6O77

Structure of the TRPM8 cold receptor by single particle electron cryo-microscopy, calcium-bound state

6O77 の概要

• エントリーDOI: 10.2210/pdb6o77/pdb
• 関連するPDBエントリー: 6O6A 6O6R 6O72
• EMDBエントリー: 0631 0636 0638 0639
• 分子名称: Transient receptor potential cation channel subfamily M member 8, CALCIUM ION, CHOLESTEROL HEMISUCCINATE (3 entities in total)
• 機能のキーワード: transport protein, ion channel, trpm8
• 由来する生物種: Parus major (Great Tit)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 513960.21

構造登録者

Diver, M.M.,Cheng, Y.,Julius, D. (登録日: 2019-03-07, 公開日: 2019-09-18, 最終更新日: 2024-11-20)

主引用文献

Diver, M.M.,Cheng, Y.,Julius, D.
Structural insights into TRPM8 inhibition and desensitization.
Science, 365:1434-1440, 2019

PubMed Abstract: The transient receptor potential melastatin 8 (TRPM8) ion channel is the primary detector of environmental cold and an important target for treating pathological cold hypersensitivity. Here, we present cryo-electron microscopy structures of TRPM8 in ligand-free, antagonist-bound, or calcium-bound forms, revealing how robust conformational changes give rise to two nonconducting states, closed and desensitized. We describe a malleable ligand-binding pocket that accommodates drugs of diverse chemical structures, and we delineate the ion permeation pathway, including the contribution of lipids to pore architecture. Furthermore, we show that direct calcium binding mediates stimulus-evoked desensitization, clarifying this important mechanism of sensory adaptation. We observe large rearrangements within the S4-S5 linker that reposition the S1-S4 and pore domains relative to the TRP helix, leading us to propose a distinct model for modulation of TRPM8 and possibly other TRP channels.

PubMed: 31488702
DOI: 10.1126/science.aax6672

実験手法

ELECTRON MICROSCOPY (3.2 Å)