6pqp
Cryo-EM structure of the human TRPA1 ion channel in complex with the covalent agonist BITC
Structural highlights
Disease[TRPA1_HUMAN] Familial episodic pain syndrome with predominantly upper body involvement. The disease is caused by mutations affecting the gene represented in this entry. Function[TRPA1_HUMAN] Receptor-activated non-selective cation channel involved in detection of pain and possibly also in cold perception and inner ear function (PubMed:25389312, PubMed:25855297). Has a central role in the pain response to endogenous inflammatory mediators and to a diverse array of volatile irritants, such as mustard oil, cinnamaldehyde, garlic and acrolein, an irritant from tears gas and vehicule exhaust fumes (PubMed:25389312, PubMed:20547126). Is also activated by menthol (in vitro)(PubMed:25389312). Acts also as an ionotropic cannabinoid receptor by being activated by delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana (PubMed:25389312). May be a component for the mechanosensitive transduction channel of hair cells in inner ear, thereby participating in the perception of sounds. Probably operated by a phosphatidylinositol second messenger system (By similarity).[UniProtKB:Q8BLA8][1] [2] [3] Publication Abstract from PubMedTransient receptor potential channel subfamily A member 1 (TRPA1) is a Ca(2+)-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 A, 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. Structural Insights into Electrophile Irritant Sensing by the Human TRPA1 Channel.,Suo Y, Wang Z, Zubcevic L, Hsu AL, He Q, Borgnia MJ, Ji RR, Lee SY Neuron. 2019 Dec 6. pii: S0896-6273(19)31009-8. doi:, 10.1016/j.neuron.2019.11.023. PMID:31866091[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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