2mfa

Mambalgin-2Mambalgin-2

Structural highlights 2mfa is a 1 chain structure with sequence from Dendroaspis polylepis polylepis. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Solution NMR, 20 models Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function 3SX2_DENPO This three-finger toxin inhibits ASIC channels. It acts as a gating modifier toxin by decreasing the apparent proton sensitivity of activation and by slightly increasing the apparent proton sensitivity for inactivation (PubMed:24695733). It binds more tightly to the closed state and to a much lesser extent the inactivated/desensitized state of ASIC1a isoform of ASIC1 (PubMed:24695733). It interacts directly with the outside surface of the thumb domain of chicken ASIC1a (ASIC1a), but does not insert into the acidic pocket as suggested previously (By similarity). This binding leads to relocation of the thumb domain that could disrupt the acidic pocket of cASIC1a (By similarity). The peptide exerts both stimulatory and inhibitory effects on ASIC1a (PubMed:24695733). It reversibly inhibits rat ASIC1a (IC(50)=21-55 nM), rat ASIC1b (IC(50)=103-192 nM), rat ASIC1a-ASIC1b (IC(50)=72 nM), rat ASIC1a-ASIC2a (IC(50)=246-252 nM) and rat ASIC1a-ASIC2b (IC(50)=61 nM) (PubMed:23034652, PubMed:23624383, PubMed:24323786, PubMed:24695733, PubMed:26991634). In vivo, it shows a potent naloxone-resistant analgesic effect against acute and inflammatory pain upon central and peripheral injection (By similarity). In addition, it also has an opioid-independent effect on both thermal and mechanical inflammatory pain after systemic administration and is effective against neuropathic pain (By similarity).[UniProtKB:P0DKR6] Publication Abstract from PubMed Mambalgins are a novel class of snake venom components that exert potent analgesic effects mediated through the inhibition of acid-sensing ion channels (ASICs). The 57-residue polypeptide mambalgin-2 (Ma-2) was synthesized by using a combination of solid-phase peptide synthesis and native chemical ligation. The structure of the synthetic toxin, determined using homonuclear NMR, revealed an unusual three-finger toxin fold reminiscent of functionally unrelated snake toxins. Electrophysiological analysis of Ma-2 on wild-type and mutant ASIC1a receptors allowed us to identify alpha-helix 5, which borders on the functionally critical acidic pocket of the channel, as a major part of the Ma-2 binding site. This region is also crucial for the interaction of ASIC1a with the spider toxin PcTx1, thus suggesting that the binding sites for these toxins substantially overlap. This work lays the foundation for structure-activity relationship (SAR) studies and further development of this promising analgesic peptide. Chemical Synthesis, 3D Structure, and ASIC Binding Site of the Toxin Mambalgin-2.,Schroeder CI, Rash LD, Vila-Farres X, Rosengren KJ, Mobli M, King GF, Alewood PF, Craik DJ, Durek T Angew Chem Int Ed Engl. 2013 Dec 9. doi: 10.1002/anie.201308898. PMID:24323786 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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