6PQO

Cryo-EM structure of the human TRPA1 ion channel in complex with the covalent agonist JT010

Summary for 6PQO

• Entry DOI: 10.2210/pdb6pqo/pdb
• EMDB information: 20449 20450 20451
• Descriptor: Transient receptor potential cation channel subfamily A member 1, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-chloro-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-N-(3-methoxypropyl)acetamide, ... (5 entities in total)
• Functional Keywords: ion channel, trp channel, trpa channel, trpa1 channel, irritant sensing, jt010, membrane protein, transport protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 546667.74

Authors

Suo, Y.,Wang, Z.,Zubcevic, L.,Hsu, A.L.,He, Q.,Borgnia, M.J.,Ji, R.-R.,Lee, S.-Y. (deposition date: 2019-07-09, release date: 2020-01-08, Last modification date: 2024-10-09)

Primary citation

Suo, Y.,Wang, Z.,Zubcevic, L.,Hsu, A.L.,He, Q.,Borgnia, M.J.,Ji, R.R.,Lee, S.Y.
Structural Insights into Electrophile Irritant Sensing by the Human TRPA1 Channel.
Neuron, 105:882-, 2020

PubMed Abstract: Transient receptor potential channel subfamily A member 1 (TRPA1) is a Ca-permeable cation channel that serves as one of the primary sensors of environmental irritants and noxious substances. Many TRPA1 agonists are electrophiles that are recognized by TRPA1 via covalent bond modifications of specific cysteine residues located in the cytoplasmic domains. However, a mechanistic understanding of electrophile sensing by TRPA1 has been limited due to a lack of high-resolution structural information. Here, we present the cryoelectron microscopy (cryo-EM) structures of nanodisc-reconstituted ligand-free TRPA1 and TRPA1 in complex with the covalent agonists JT010 and BITC at 2.8, 2.9, and 3.1 Å, respectively. Our structural and functional studies provide the molecular basis for electrophile recognition by the extraordinarily reactive C621 in TRPA1 and mechanistic insights into electrophile-dependent conformational changes in TRPA1. This work also provides a platform for future drug development targeting TRPA1.

PubMed: 31866091
DOI: 10.1016/j.neuron.2019.11.023

Experimental method

ELECTRON MICROSCOPY (2.88 Å)