Structure of the TRPA1 ion channel suggests regulatory mechanisms

By C. E. Paulsen, Jean-Paul Armache, Yuan Gao, Yifan Cheng, D. Julius. Nature, 2015

656 citations recorded by the source corpus.

The TRPA1 ion channel (also known as the wasabi receptor) is a detector of noxious chemical agents encountered in our environment or produced endogenously during tissue injury or drug metabolism. These include a broad class of electrophiles that activate the channel through covalent protein modification. TRPA1 antagonists hold potential for treating neurogenic inflammatory conditions provoked or exacerbated by irritant exposure. Despite compelling reasons to understand TRPA1 function, structural mechanisms underlying channel regulation remain obscure. Here we use single-particle electron cryo- microscopy to determine the structure of full-length human TRPA1 to ∼4 Å resolution in the presence of pharmacophores, including a potent antagonist. Several unexpected features are revealed, including an extensive coiled-coil assembly domain stabilized by polyphosphate co-factors and a highly integrated nexus that converges on an unpredicted transient receptor potential (TRP)-like allosteric domain. These findings provide new insights into the mechanisms of TRPA1 regulation, and establish a blueprint for structure-based design of analgesic and anti-inflammatory agents.

Subfields: Plant Science, Sensory Systems

View Paper: https://www.semanticscholar.org/paper/395c9f6aedeb07635f315d0e22e49d6fed449d5d

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Citations in the corpus

• Oxidative Stress in Cancer (2020, background): “Cryoelectron microscopy has confirmed that Cys-621, Cys-641, and Cys-665 are highly reactive (Paulsen et al., 2015), but further experiments are required to determine how TRP channels are activated by ROS/RNS.”
• Gctf: Real-time CTF determination and correction (2015, background): “More and more structures at near-atomic or atomic resolution are being solved recently by cryoEM (Amunts et al., 2015; Bartesaghi et al., 2015; Jiang et al., 2015; Paulsen et al., 2015; Taylor et al., 2015; Urnavicius et al., 2015; Zhao et al., 2015).”
• Non-uniform refinement: adaptive regularization improves single-particle cryo-EM reconstruction (2019, background): “1, with the TRPA1 membrane protein [21], over-fitting occurs in the disordered micelle and in the dynamic tail at the bottom of the protein.”