9M8S

Cryo-EM structure of the human TRPA1 ion channel in ligand-free state.

9M8S の概要

• エントリーDOI: 10.2210/pdb9m8s/pdb
• EMDBエントリー: 63720
• 分子名称: Transient receptor potential cation channel subfamily A member 1 (1 entity in total)
• 機能のキーワード: transport protein, membrane 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: 510642.28

構造登録者

Kang, M.M.,Zhang, Y.M.,Ding, X.F.,Wang, L.J.,Sun, W.Y.,Jiang, H.,Chen, D.,Xu, J.F.,Pang, X.Y. (登録日: 2025-03-12, 公開日: 2025-10-29)

主引用文献

Kang, M.,Zhang, Y.,Ding, X.,Xu, J.,Pang, X.
Binding and Activating of Analgesic Crotalphine with Human TRPA1.
Membranes (Basel), 15:-, 2025

PubMed Abstract: TRPA1 (Transient Receptor Potential Ankyrin 1), a cation channel predominantly expressed in sensory neurons, plays a critical role in detecting noxious stimuli and mediating pain signal transmission. As a key player in nociceptive signaling pathways, TRPA1 has emerged as a promising therapeutic target for the development of novel analgesics. Crotalphine (CRP), a 14-amino acid peptide, has been demonstrated to specifically activate TRPA1 and elicit potent analgesic effects. Previous cryo-EM (cryo-electron microscopy) studies have elucidated the structural mechanisms of TRPA1 activation by small-molecule agonists, such as iodoacetamide (IA), through covalent modification of N-terminal cysteine residues. However, the molecular interactions between TRPA1 and peptide ligands, including crotalphine, remain unclear. Here, we present the cryo-EM structure of ligand-free human TRPA1 consistent with the literature, as well as TRPA1 complexed with crotalphine, with resolutions of 3.1 Å and 3.8 Å, respectively. Through a combination of single-particle cryo-EM studies, patch-clamp electrophysiology, and microscale thermophoresis (MST), we have identified the cysteine residue at position 621 (Cys621) within the TRPA1 ion channel as the primary binding site for crotalphine. Upon binding to the reactive pocket containing C621, crotalphine induces rotational and translational movements of the transmembrane domain. This allosteric modulation coordinately dilates both the upper and lower gates, facilitating ion permeation.

PubMed: 40559366
DOI: 10.3390/membranes15060187

実験手法

ELECTRON MICROSCOPY (3.1 Å)