Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland (Australia).
Angew Chem Int Ed Engl. 2014 Jan 20;53(4):1017-20. doi: 10.1002/anie.201308898. Epub 2013 Dec 9.
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 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. This work lays the foundation for structure-activity relationship (SAR) studies and further development of this promising analgesic peptide.
曼巴毒素是一类新型的蛇毒成分，通过抑制酸感应离子通道 (ASICs) 发挥强效的镇痛作用。由固相肽合成和天然化学连接组合合成的 57 个残基多肽曼巴毒素-2（Ma-2）。使用同核 NMR 确定的合成毒素结构揭示了一种不寻常的三指毒素折叠，类似于功能上不相关的蛇毒素。Ma-2 在野生型和突变型 ASIC1a 受体上的电生理分析使我们能够确定α-螺旋 5，它与通道的功能关键酸性口袋相邻，是 Ma-2 结合位点的主要部分。该区域对于 ASIC1a 与蜘蛛毒素 PcTx1 的相互作用也至关重要，因此表明这些毒素的结合位点基本重叠。这项工作为结构-活性关系（SAR）研究和这种有前途的镇痛肽的进一步开发奠定了基础。
