6V9V

Structure of TRPA1 modified by Bodipy-iodoacetamide with bound calcium, LMNG

6V9V の概要

• エントリーDOI: 10.2210/pdb6v9v/pdb
• EMDBエントリー: 21127 21128 21129 21130 21131 21537 21538
• 分子名称: Transient receptor potential cation channel subfamily A member 1, ~{N}-[[2,2-bis(fluoranyl)-10,12-dimethyl-1,3-diaza-2$l^{4}-boratricyclo[7.3.0.0^{3,7}]dodeca-4,6,9,11-tetraen-4-yl]methyl]ethanamide, CALCIUM ION (3 entities in total)
• 機能のキーワード: transient receptor potential subfamily a member 1, membrane protein, 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: 511914.92

構造登録者

Zhao, J.,Lin King, J.V.,Paulsen, C.E.,Cheng, Y.,Julius, D. (登録日: 2019-12-16, 公開日: 2020-05-06, 最終更新日: 2024-11-06)

主引用文献

Zhao, J.,Lin King, J.V.,Paulsen, C.E.,Cheng, Y.,Julius, D.
Irritant-evoked activation and calcium modulation of the TRPA1 receptor.
Nature, 585:141-145, 2020

PubMed Abstract: The transient receptor potential ion channel TRPA1 is expressed by primary afferent nerve fibres, in which it functions as a low-threshold sensor for structurally diverse electrophilic irritants, including small volatile environmental toxicants and endogenous algogenic lipids. TRPA1 is also a 'receptor-operated' channel whose activation downstream of metabotropic receptors elicits inflammatory pain or itch, making it an attractive target for novel analgesic therapies. However, the mechanisms by which TRPA1 recognizes and responds to electrophiles or cytoplasmic second messengers remain unknown. Here we use strutural studies and electrophysiology to show that electrophiles act through a two-step process in which modification of a highly reactive cysteine residue (C621) promotes reorientation of a cytoplasmic loop to enhance nucleophilicity and modification of a nearby cysteine (C665), thereby stabilizing the loop in an activating configuration. These actions modulate two restrictions controlling ion permeation, including widening of the selectivity filter to enhance calcium permeability and opening of a canonical gate at the cytoplasmic end of the pore. We propose a model to explain functional coupling between electrophile action and these control points. We also characterize a calcium-binding pocket that is highly conserved across TRP channel subtypes and accounts for all aspects of calcium-dependent TRPA1 regulation, including potentiation, desensitization and activation by metabotropic receptors. These findings provide a structural framework for understanding how a broad-spectrum irritant receptor is controlled by endogenous and exogenous agents that elicit or exacerbate pain and itch.

PubMed: 32641835
DOI: 10.1038/s41586-020-2480-9

実験手法

ELECTRON MICROSCOPY (2.6 Å)