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Publication Abstract from PubMed

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 pi-TRTX-Pc1a (PcTx1), a disulfide-rich 40-residue peptide isolated from spider venom. pi-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 pi-TRTX-Pc1a-ASIC1a interaction should facilitate development of therapeutically useful ASIC1a blockers. We therefore developed an efficient bacterial expression system to produce a panel of pi-TRTX-Pc1a mutants for probing structure-activity relationships as well as isotopically labeled toxin for determination of its solution structure and dynamics. We demonstrate that the toxin pharmacophore resides in a beta-hairpin loop that was revealed to be mobile over a wide range of time scales 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 pi-TRTX-Pc1a and provides an experimentally validated template for the rational design of therapeutically useful pi-TRTX-Pc1a mimetics.

A dynamic pharmacophore drives the interaction between Psalmotoxin-1 and the putative drug target acid-sensing ion channel 1a.,Saez NJ, Mobli M, Bieri M, Chassagnon IR, Malde AK, Gamsjaeger R, Mark AE, Gooley PR, Rash LD, King GF Mol Pharmacol. 2011 Nov;80(5):796-808. doi: 10.1124/mol.111.072207. Epub 2011 Aug, 8. PMID:21825095^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.