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PMID: 25855297 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Structure of the TRPA1 ion channel suggests regulatory mechanisms.

Nature ·Vol. 520 ·No. 7548 ·2015-04-23 ·Pages 511-7

Paulsen CE, Armache JP, Gao Y, Cheng Y, Julius D

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.

MeSH Terms
Allosteric Regulation Analgesics Ankyrin Repeat Anti-Inflammatory Agents Binding Sites Calcium Channels/chemistry,metabolism,ultrastructure Cryoelectron Microscopy Cytosol/metabolism Humans Models, Molecular Nerve Tissue Proteins/antagonists & inhibitors,chemistry,metabolism,ultrastructure Polyphosphates/metabolism,pharmacology Protein Stability/drug effects Protein Subunits/chemistry,metabolism Structure-Activity Relationship TRPA1 Cation Channel Transient Receptor Potential Channels/antagonists & inhibitors,chemistry,metabolism,ultrastructure
Chemicals
Analgesics Anti-Inflammatory Agents Calcium Channels Nerve Tissue Proteins Polyphosphates Protein Subunits TRPA1 Cation Channel TRPA1 protein, human Transient Receptor Potential Channels
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Paulsen Candice E
Department of Physiology, University of California, San Francisco, California 94158-2517, USA.
Armache Jean-Paul
Keck Advanced Microscopy Laboratory, Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158-2517, USA.
Gao Yuan
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.
Cheng Yifan
Keck Advanced Microscopy Laboratory, Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158-2517, USA.
Julius David
Department of Physiology, University of California, San Francisco, California 94158-2517, USA.
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature14367
Published
2015-04-23
Epub
2015-00-08
Pages
511-7
Language
English
Region
England
NLM ID
0410462
PMCID
PMC4409540
Subset
IM
Grants
NIGMS NIH HHS · T32 GM008284 · United States
NIBIB NIH HHS · T32 EB009383 · United States
NINDS NIH HHS · R01NS055299 · United States
NINDS NIH HHS · R01 NS055299 · United States
Howard Hughes Medical Institute · United States
NIGMS NIH HHS · R01GM098672 · United States
NIGMS NIH HHS · R01 GM098672 · United States
Databases
PDB
3J9P
Corrections
CommentIn
PMID: 25855290
ErratumIn
PMID: 26200340
External Links
PubMed source DOI: 10.1038/nature14367 PMC Full Text View journal details
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