Structure of the TRPA1 ion channel suggests regulatory mechanisms

• Published in: Nature (London) Vol. 520; no. 7548; pp. 511 - 517
• Main Authors: Paulsen, Candice E., Armache, Jean-Paul, Gao, Yuan, Cheng, Yifan, Julius, David
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.04.2015; Nature Publishing Group
• Subjects: 631/92/269/1153; Allosteric Regulation; Analgesics; Ankyrin Repeat; Anti-Inflammatory Agents; Binding Sites; Biological control systems; Calcium Channels - chemistry; Calcium Channels - metabolism; Calcium Channels - ultrastructure; Cellular biology; Chemical agents; Cryoelectron Microscopy; Cytosol - metabolism; Humanities and Social Sciences; Humans; Ion channels; Ions; Models, Molecular; multidisciplinary; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - metabolism; Nerve Tissue Proteins - ultrastructure; Observations; Physiological aspects; Polyphosphates - metabolism; Polyphosphates - pharmacology; Protein Stability - drug effects; Protein Subunits - chemistry; Protein Subunits - metabolism; Proteins; Science; Structure; Structure-Activity Relationship; Transient Receptor Potential Channels - antagonists & inhibitors; Transient Receptor Potential Channels - chemistry; Transient Receptor Potential Channels - metabolism; Transient Receptor Potential Channels - ultrastructure; TRPA1 Cation Channel; United States
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature14367

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. The high-resolution electron cryo-microscopy structure of the full-length human TRPA1 ion channel is presented; the structure reveals a unique ankyrin repeat domain arrangement, a tetrameric coiled-coil in the centre of the channel that acts as a binding site for inositol hexakisphosphate, an outer poor domain with two pore helices, and a new drug binding site, findings that collectively provide mechanistic insight into TRPA1 regulation. Structure of multifunctional TRPA1 receptor TRP (transient receptor potential) channels are expressed by all eukaryotic organisms and act as sensors for a wide range of physical and chemical stimuli. This paper reports the high-resolution electron cryomicroscopy structure of full-length human TRPA1, a sensory receptor for noxious chemical agents such as wasabi. The overall structure of this membrane protein differs markedly from the previously published structure of TRPV1, as TRPA1 has many ankyrin repeat domains, a tetrameric coiled-coil in the center of the channel that appears to serve as a binding site for inositol hexakisphosphate and an outer pore domain with two pore helices. TRPA1 is associated with persistent pain, respiratory and chronic itch syndromes, so TRPA1 antagonists are of interest as potential analgesics.