EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Irritant-evoked activation and calcium modulation of the TRPA1 receptor.
ジャーナル・号・ページ	Nature, Vol. 585, Issue 7823, Page 141-145, Year 2020
掲載日	2020年7月8日
著者	Jianhua Zhao / John V Lin King / Candice E Paulsen / Yifan Cheng / David Julius /
PubMed 要旨	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, ...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.
リンク	Nature / PubMed:32641835 / PubMed Central
手法	EM (単粒子)
解像度	2.6 - 5.9 Å
構造データ	21127 6v9v EMDB-21127, PDB-6v9v: Structure of TRPA1 modified by Bodipy-iodoacetamide with bound calcium, LMNG 手法: EM (単粒子) / 解像度: 2.6 Å 21128 6v9w EMDB-21128, PDB-6v9w: Structure of TRPA1 (ligand-free) with bound calcium, LMNG 手法: EM (単粒子) / 解像度: 3.1 Å 21129 6v9x EMDB-21129, PDB-6v9x: Structure of TRPA1 modified by iodoacetamide, PMAL-C8 手法: EM (単粒子) / 解像度: 3.3 Å 21130 6v9y EMDB-21130, PDB-6v9y: Structure of TRPA1 bound with A-967079, PMAL-C8 手法: EM (単粒子) / 解像度: 3.6 Å EMDB-21131: Structure of TRPA1 treated with A-967079 (class 2), PMAL-C8 手法: EM (単粒子) / 解像度: 3.5 Å EMDB-21537: TRPA1 (ligand-free and calcium-free) in PMAL-C8, class 1 手法: EM (単粒子) / 解像度: 5.9 Å EMDB-21538: Structure of TRPA1 (ligand-free and calcium-free), PMAL-C8, class 2 手法: EM (単粒子) / 解像度: 4.3 Å
化合物	ChemComp-QT4: ~{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 ChemComp-CA: Unknown entry / カルシウムジカチオン
由来	homo sapiens (ヒト)
キーワード	TRANSPORT PROTEIN (運搬体タンパク質) / transient receptor potential subfamily A member 1 / Membrane protein (膜タンパク質) / Transient receptor potential cation channel subfamily A member 1