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基本情報
登録情報 | データベース: PDB / ID: 6v9v | |||||||||
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タイトル | Structure of TRPA1 modified by Bodipy-iodoacetamide with bound calcium, LMNG | |||||||||
![]() | Transient receptor potential cation channel subfamily A member 1 | |||||||||
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機能・相同性 | ![]() temperature-gated cation channel activity / stereocilium bundle / detection of chemical stimulus involved in sensory perception of pain / ![]() ![]() ![]() ![]() ![]() ![]() ![]() 類似検索 - 分子機能 | |||||||||
生物種 | ![]() ![]() | |||||||||
手法 | ![]() ![]() ![]() | |||||||||
![]() | Zhao, J. / Lin King, J.V. / Paulsen, C.E. / Cheng, Y. / Julius, D. | |||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Irritant-evoked activation and calcium modulation of the TRPA1 receptor. 著者: Jianhua Zhao / John V Lin King / Candice E Paulsen / Yifan Cheng / David Julius / ![]() 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. | |||||||||
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構造の表示
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構造ビューア | 分子: ![]() ![]() |
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-関連構造データ
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リンク
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集合体
登録構造単位 | ![]()
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要素
#1: タンパク質 | 分子量: 127646.539 Da / 分子数: 4 / 変異: D966E / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() ![]() #2: 化合物 | ChemComp-QT4 / ~{ #3: 化合物 | ChemComp-CA / 研究の焦点であるリガンドがあるか | Y | |
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-実験情報
-実験
実験 | 手法: ![]() |
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EM実験 | 試料の集合状態: PARTICLE / 3次元再構成法: ![]() |
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試料調製
構成要素 | 名称: TRPA1 modified by Bodipy-iodoacetamide with bound calcium, solubilized in LMNG タイプ: COMPLEX / Entity ID: #1 / 由来: RECOMBINANT |
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由来(天然) | 生物種: ![]() ![]() |
由来(組換発現) | 生物種: ![]() ![]() |
緩衝液 | pH: 8 |
試料 | 包埋: NO / シャドウイング: NO / 染色![]() ![]() |
試料支持 | 詳細: unspecified |
急速凍結![]() | 凍結剤: ETHANE |
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電子顕微鏡撮影
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
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顕微鏡 | モデル: FEI TITAN KRIOS |
電子銃 | 電子線源![]() ![]() |
電子レンズ | モード: BRIGHT FIELD![]() |
撮影 | 電子線照射量: 25 e/Å2 / 検出モード: SUPER-RESOLUTION フィルム・検出器のモデル: GATAN K2 SUMMIT (4k x 4k) |
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解析
CTF補正![]() | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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対称性 | 点対称性![]() ![]() |
3次元再構成![]() | 解像度: 2.6 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 212751 / 対称性のタイプ: POINT |