title: Structure of the TRPA1 ion channel suggests regulatory mechanisms.
abstract: 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.
authors: Department of Physiology, University of California, San Francisco, California 94158-2517, USA.
authors: Candice E
authors: CE
authors: Paulsen
authors: Keck Advanced Microscopy Laboratory, Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158-2517, USA.
authors: Jean-Paul
authors: JP
authors: Armache
authors: 1] Department of Physiology, University of California, San Francisco, California 94158-2517, USA [2] Keck Advanced Microscopy Laboratory, Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158-2517, USA.
authors: Yuan
authors: Y
authors: Gao
authors: Keck Advanced Microscopy Laboratory, Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158-2517, USA.
authors: Yifan
authors: Y
authors: Cheng
authors: Department of Physiology, University of California, San Francisco, California 94158-2517, USA.
authors: David
authors: D
authors: Julius
mesh_terms: D000494:Allosteric Regulation; D000700:Analgesics; D017089:Ankyrin Repeat; D000893:Anti-Inflammatory Agents; D001665:Binding Sites; D015220:Calcium Channels / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure*; D020285:Cryoelectron Microscopy; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure*; D011122:Polyphosphates / Q000378:metabolism / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure*
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D015220:Calcium Channels; D009419:Nerve Tissue Proteins; D011122:Polyphosphates; D021122:Protein Subunits; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050051:Transient Receptor Potential Channels