8.A.23 The Mambalgin (Mambalgin) Family Mambalgins are a novel class of snake venom components that exert potent analgesic effects mediated through the inhibition of acid-sensing ion channels (ASICs; TC# 1.A.6). 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 (Schroeder et al. 2014). Electrophysiological analysis of Ma-2 on wild-type and mutant ASIC1a receptors allowed the identification of α-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. The binding site and mechanism of inhibition on ASIC1a has been determined, and it binding accounts for its pain relieving activity (Salinas et al. 2014).
This family belongs to the Aerolysin Superfamily.
References:
Escoubas, P., C. Bernard, G. Lambeau, M. Lazdunski, and H. Darbon. (2003). Recombinant production and solution structure of PcTx1, the specific peptide inhibitor of ASIC1a proton-gated cation channels. Protein. Sci. 12: 1332-1343.
Escoubas, P., J.R. De Weille, A. Lecoq, S. Diochot, R. Waldmann, G. Champigny, D. Moinier, A. Ménez, and M. Lazdunski. (2000). Isolation of a tarantula toxin specific for a class of proton-gated Na⁺ channels. J. Biol. Chem. 275: 25116-25121.
Kuhn, P., A.M. Deacon, S. Comoso, G. Rajaseger, R.M. Kini, I. Usón, and P.R. Kolatkar. (2000). The atomic resolution structure of bucandin, a novel toxin isolated from the Malayan krait, determined by direct methods. Acta Crystallogr D Biol Crystallogr 56: 1401-1407.
Rivera-Torres, I.O., T.B. Jin, M. Cadene, B.T. Chait, and S.F. Poget. (2016). Discovery and characterisation of a novel toxin from Dendroaspis angusticeps, named Tx7335, that activates the potassium channel KcsA. Sci Rep 6: 23904.
Salinas, M., T. Besson, Q. Delettre, S. Diochot, S. Boulakirba, D. Douguet, and E. Lingueglia. (2014). Binding site and inhibitory mechanism of the mambalgin-2 pain-relieving peptide on acid-sensing ion channel 1a. J. Biol. Chem. 289: 13363-13373.
Schroeder, C.I., L.D. Rash, X. Vila-Farrés, K.J. Rosengren, M. Mobli, G.F. King, P.F. Alewood, D.J. Craik, and T. Durek. (2014). Chemical synthesis, 3D structure, and ASIC binding site of the toxin mambalgin-2. Angew Chem Int Ed Engl 53: 1017-1020.
Examples:
TC#	Name	Organismal Type	Example
8.B.23.1.1	Mambalgin 1 of 78 aas	Spiders	*Mambalgin 1 of Dendroaspis polylepis polylepis* (Black mamba)**

8.B.23.1.2	Mambalgin 2 of 57 aas	Spiders	*Mambalgin 2 of Dendroaspis polylepis polylepis* (Black mamba)**

8.B.23.1.3	Mambalgin 3 of 57 aas	Spiders	Mambalgin 3 of Dendroaspis angusticeps (Eastern green mamba) (Naja angusticeps)

8.B.23.1.4	Short neurotoxin MS11 of 58 aas	Snakes	*MS11 of Micrurus surinamensis* (Surinam coral snake)**

Examples:
TC#	Name	Organismal Type	Example
8.B.23.2.1	Tx7335 of 63 aas and 1 or 2 TMSs from eastern green mamba snake venom. This toxin activates the potassium channel, KcsA (TC#1.A.1.1.1) (Rivera-Torres et al. 2016). It induces a dose-dependent increase in both open probabilities and mean open times on KcsA in artificial bilayers. The extracellular binding site for Tx7335 is distinct from that of canonical pore-blocker toxins (Rivera-Torres et al. 2016).		Tx7335 of Dendroaspis angusticeps

8.B.23.2.2	Three finger toxin precursor of 84 aas and 1 N-terminal TMS.		Toxin of Micrurus altirostris

8.B.23.2.3	*Presynaptic neurotoxin, Bucandin of 63 aas. It enhances presynaptic acetylcholine release. The structure is known (Kuhn et al.* 2000).**		Bucandin of Bungarus candidus (Malayan krait)