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Elife. 2016 Feb 10;5. pii: e11273. doi: 10.7554/eLife.11273.

Structural insights into the mechanism of activation of the TRPV1 channel by a membrane-bound tarantula toxin.

Author information

1
Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States.
2
Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
3
Theoretical Molecular Biophysics Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United States.
4
Indian Institute of Science Education and Research, Pune, Pune, India.
5
Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, United States.
6
Department of Chemistry, Chonnam National University, Gwanju, Republic of Korea.
7
Protein Structure Research Group, Korea Basic Science Institute, Ochang, Republic of Korea.

Abstract

Venom toxins are invaluable tools for exploring the structure and mechanisms of ion channels. Here, we solve the structure of double-knot toxin (DkTx), a tarantula toxin that activates the heat-activated TRPV1 channel. We also provide improved structures of TRPV1 with and without the toxin bound, and investigate the interactions of DkTx with the channel and membranes. We find that DkTx binds to the outer edge of the external pore of TRPV1 in a counterclockwise configuration, using a limited protein-protein interface and inserting hydrophobic residues into the bilayer. We also show that DkTx partitions naturally into membranes, with the two lobes exhibiting opposing energetics for membrane partitioning and channel activation. Finally, we find that the toxin disrupts a cluster of hydrophobic residues behind the selectivity filter that are critical for channel activation. Collectively, our findings reveal a novel mode of toxin-channel recognition that has important implications for the mechanism of thermosensation.

KEYWORDS:

biophysics; capsaicin; membrane channel; membrane structure; protein-protein interactions in membranes; rat; structural biology; thermosensing

PMID:
26880553
PMCID:
PMC4764579
DOI:
10.7554/eLife.11273
[Indexed for MEDLINE]
Free PMC Article

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