A dynamic pharmacophore drives the interaction between psalmotoxin-1 and the putative drug target acid-sensing ion channel 1a

Saez, Natalie J., Mobli, Mehdi, Bieri, Michael, Chassagnon, Irene R., Malde, Alpeshkumar K., Gamsjaeger, Roland, Mark, Alan E., Gooley, Paul R., Rash. Lachlan D. and King, Glenn F. (2011) A dynamic pharmacophore drives the interaction between psalmotoxin-1 and the putative drug target acid-sensing ion channel 1a. Molecular Pharmacology, 80 5: 796-808. doi:10.1124/mol.111.072207

Author Saez, Natalie J.
Mobli, Mehdi
Bieri, Michael
Chassagnon, Irene R.
Malde, Alpeshkumar K.
Gamsjaeger, Roland
Mark, Alan E.
Gooley, Paul R.
Rash. Lachlan D.
King, Glenn F.
Title A dynamic pharmacophore drives the interaction between psalmotoxin-1 and the putative drug target acid-sensing ion channel 1a
Journal name Molecular Pharmacology   Check publisher's open access policy
ISSN 0026-895X
Publication date 2011-08-08
Sub-type Article (original research)
DOI 10.1124/mol.111.072207
Volume 80
Issue 5
Start page 796
End page 808
Total pages 50
Place of publication Bethesda, MD, United States
Publisher American Society for Pharmacology and Experimental Therapeutics
Collection year 2012
Language eng
Formatted abstract
Acid-sensing ion channel 1a (ASIC1a) is a primary acid sensor in the peripheral and central nervous system. It has been implicated as a novel therapeutic target for a broad range of pathophysiological conditions including pain, ischemic stroke, depression, and autoimmune diseases such as multiple sclerosis. The only known selective blocker of ASIC1a is π-TRTX-Pc1a (PcTx1), a disulfide-rich 40-residue peptide isolated from spider venom. π-TRTX-Pc1a is an effective analgesic in rodent models of acute pain and it provides neuroprotection in a mouse model of ischemic stroke. Thus, understanding the molecular basis of the π-TRTX-Pc1a:ASIC1a interaction should facilitate development of therapeutically useful ASIC1a blockers. We therefore developed an efficient bacterial expression system in order to produce a panel of π-TRTX-Pc1a mutants for probing structure-activity relationships as well isotopically-labeled toxin for determination of its solution structure and dynamics. We demonstrate that the toxin pharmacophore resides in a β-hairpin loop that was revealed to be mobile over a wide range of timescales using molecular dynamics simulations in combination with NMR spin relaxation and relaxation dispersion measurements. The toxin:receptor interaction was modeled by in silico docking of the toxin structure onto a homology model of rat ASIC1a in a restraints-driven approach that was designed to take account of the dynamics of the toxin pharmacophore and the consequent remodeling of side-chain conformations upon receptor binding. The resulting model reveals new insights into the mechanism of action of π-TRTX-Pc1a and provides an experimentally validated template for the rational design of therapeutically useful π-TRTX-Pc1a mimetics.
Keyword Ion channel regulation
Molecular dynamics
Structure determinations
Structure-activity relationships and modeling
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes "Fast Forward" Published online before print August 8, 2011. MOL #72207.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
School of Chemistry and Molecular Biosciences
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 41 times in Thomson Reuters Web of Science Article | Citations
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Created: Mon, 05 Sep 2011, 23:55:21 EST by Dr Lachlan Rash on behalf of Institute for Molecular Bioscience