Structure of the Acid-sensing ion channel 1 in complex with the gating modifier Psalmotoxin 1

Roger J.P. Dawson (), Jörg Benz, Peter Stohler, Tim Tetaz, Catherine Joseph, Sylwia Huber, Georg Schmid, Daniela Hügin, Pascal Pflimlin, Gerd Trube, Markus G. Rudolph, Michael Hennig and Armin Ruf
Additional contact information
Roger J.P. Dawson: F. Hoffmann-La Roche AG, pRED, Pharma Research & Early Development, Discovery Technologies
Jörg Benz: F. Hoffmann-La Roche AG, pRED, Pharma Research & Early Development, Discovery Technologies
Peter Stohler: F. Hoffmann-La Roche AG, pRED, Pharma Research & Early Development, Discovery Technologies
Tim Tetaz: F. Hoffmann-La Roche AG, pRED, Pharma Research & Early Development, Discovery Technologies
Catherine Joseph: F. Hoffmann-La Roche AG, pRED, Pharma Research & Early Development, Discovery Technologies
Sylwia Huber: F. Hoffmann-La Roche AG, pRED, Pharma Research & Early Development, Discovery Technologies
Georg Schmid: F. Hoffmann-La Roche AG, pRED, Pharma Research & Early Development, Discovery Technologies
Daniela Hügin: F. Hoffmann-La Roche AG, pRED, Pharma Research & Early Development, Discovery Technologies
Pascal Pflimlin: F. Hoffmann-La Roche AG, pRED, Pharma Research & Early Development, DTA CNS, Cellular Neuroscience
Gerd Trube: F. Hoffmann-La Roche AG, pRED, Pharma Research & Early Development, DTA CNS, Cellular Neuroscience
Markus G. Rudolph: F. Hoffmann-La Roche AG, pRED, Pharma Research & Early Development, Discovery Technologies
Michael Hennig: F. Hoffmann-La Roche AG, pRED, Pharma Research & Early Development, Discovery Technologies
Armin Ruf: F. Hoffmann-La Roche AG, pRED, Pharma Research & Early Development, Discovery Technologies

Nature Communications, 2012, vol. 3, issue 1, 1-8

Abstract: Abstract Venom-derived peptide toxins can modify the gating characteristics of excitatory channels in neurons. How they bind and interfere with the flow of ions without directly blocking the ion permeation pathway remains elusive. Here we report the crystal structure of the trimeric chicken Acid-sensing ion channel 1 in complex with the highly selective gating modifier Psalmotoxin 1 at 3.0 Å resolution. The structure reveals the molecular interactions of three toxin molecules binding at the proton-sensitive acidic pockets of Acid-sensing ion channel 1 and electron density consistent with a cation trapped in the central vestibule above the ion pathway. A hydrophobic patch and a basic cluster are the key structural elements of Psalmotoxin 1 binding, locking two separate regulatory regions in their relative, desensitized-like arrangement. Our results provide a general concept for gating modifier toxin binding suggesting that both surface motifs are required to modify the gating characteristics of an ion channel.

Date: 2012
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DOI: 10.1038/ncomms1917

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