2n8f | pdb_00002n8f
Chemical shift assignments and structure calculation of spider toxin pi-hexatoxin-Hi1a
Structural highlights
FunctionTP1A_HADIN This toxin potently and selectively inhibits ASIC1a (IC(50)=0.4 nM on rASIC1a and IC(50)=0.52 nM on hASIC1a), an isoform of the gene ASIC1 (PubMed:28320941). It incompletely inhibits ASIC1a activation in a pH-independent and slowly reversible manner (Tau(off)=14.2 min for rASIC1a and 31.8 min for hASIC1a) (PubMed:28320941). This toxin acts by binding to and stabilizing the closed state of the channel, thereby impeding the transition into a conducting state (PubMed:28320941). This toxin may bind to the acidic pocket of ASIC1a, since mutation of a key residue of this pocket (Arg-350) abolishes the ability of the toxin to inhibit ASIC1a (PubMed:28320941). In addition, it shows antiparasitic activities, since it moderately inhibits the larval development of the major pathogenic nematode of ruminants (H.contortus, IC(50)=22.9 uM) (PubMed:31213240). In vivo, this toxin protects the brain from neuronal injury when administered up to 8 hours after stroke onset (PubMed:28320941).[1] [2] Publication Abstract from PubMedStroke is the second-leading cause of death worldwide, yet there are no drugs available to protect the brain from stroke-induced neuronal injury. Acid-sensing ion channel 1a (ASIC1a) is the primary acid sensor in mammalian brain and a key mediator of acidosis-induced neuronal damage following cerebral ischemia. Genetic ablation and selective pharmacologic inhibition of ASIC1a reduces neuronal death following ischemic stroke in rodents. Here, we demonstrate that Hi1a, a disulfide-rich spider venom peptide, is highly neuroprotective in a focal model of ischemic stroke. Nuclear magnetic resonance structural studies reveal that Hi1a comprises two homologous inhibitor cystine knot domains separated by a short, structurally well-defined linker. In contrast with known ASIC1a inhibitors, Hi1a incompletely inhibits ASIC1a activation in a pH-independent and slowly reversible manner. Whole-cell, macropatch, and single-channel electrophysiological recordings indicate that Hi1a binds to and stabilizes the closed state of the channel, thereby impeding the transition into a conducting state. Intracerebroventricular administration to rats of a single small dose of Hi1a (2 ng/kg) up to 8 h after stroke induction by occlusion of the middle cerebral artery markedly reduced infarct size, and this correlated with improved neurological and motor function, as well as with preservation of neuronal architecture. Thus, Hi1a is a powerful pharmacological tool for probing the role of ASIC1a in acid-mediated neuronal injury and various neurological disorders, and a promising lead for the development of therapeutics to protect the brain from ischemic injury. Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1a.,Chassagnon IR, McCarthy CA, Chin YK, Pineda SS, Keramidas A, Mobli M, Pham V, De Silva TM, Lynch JW, Widdop RE, Rash LD, King GF Proc Natl Acad Sci U S A. 2017 Apr 4;114(14):3750-3755. doi:, 10.1073/pnas.1614728114. Epub 2017 Mar 20. PMID:28320941[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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