TY - JOUR T1 - A Dynamic Pharmacophore Drives the Interaction between Psalmotoxin-1 and the Putative Drug Target Acid-Sensing Ion Channel 1a JF - Molecular Pharmacology JO - Mol Pharmacol SP - 796 LP - 808 DO - 10.1124/mol.111.072207 VL - 80 IS - 5 AU - Natalie J. Saez AU - Mehdi Mobli AU - Michael Bieri AU - Irène R. Chassagnon AU - Alpeshkumar K. Malde AU - Roland Gamsjaeger AU - Alan E. Mark AU - Paul R. Gooley AU - Lachlan D. Rash AU - Glenn F. King Y1 - 2011/11/01 UR - http://molpharm.aspetjournals.org/content/80/5/796.abstract N2 - 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 to produce a panel of π-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 β-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 π-TRTX-Pc1a and provides an experimentally validated template for the rational design of therapeutically useful π-TRTX-Pc1a mimetics. ER -