2KNI
High-resolution solution structure of the ASIC1a blocker PcTX1
Summary for 2KNI
| Entry DOI | 10.2210/pdb2kni/pdb |
| Related | 1LMM |
| NMR Information | BMRB: 16468 |
| Descriptor | Psalmotoxin-1 (1 entity in total) |
| Functional Keywords | psalmotoxin 1, pi-theraphotoxin-pc1a, cystine knot, spider toxin, peptide toxin, disulfide bond, ionic channel inhibitor, knottin, neurotoxin, secreted, asic1a inhibitor, acid sensing ion channel 1a inhibitor, toxin |
| Biological source | Psalmopoeus cambridgei (Trinidad chevron tarantula) |
| Total number of polymer chains | 1 |
| Total formula weight | 4792.59 |
| Authors | King, G.F.,Mobli, M.,Saez, N.J. (deposition date: 2009-08-25, release date: 2010-09-01, Last modification date: 2024-11-20) |
| Primary citation | Saez, N.J.,Mobli, M.,Bieri, M.,Chassagnon, I.R.,Malde, A.K.,Gamsjaeger, R.,Mark, A.E.,Gooley, P.R.,Rash, L.D.,King, G.F. A dynamic pharmacophore drives the interaction between Psalmotoxin-1 and the putative drug target acid-sensing ion channel 1a. Mol.Pharmacol., 80:796-808, 2011 Cited by PubMed 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 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. PubMed: 21825095DOI: 10.1124/mol.111.072207 PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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