Choudhury Manisha, McCleary Ryan J R, Kini R Manjunatha, Velmurugan Devadasan
CAS in Crystallography and Biophysics, University of Madras, Chennai, Tamil Nadu, India.
Department of Biological Sciences, National University of Singapore, Singapore, Singapore.
TH Open. 2018 Sep 26;2(3):e303-e314. doi: 10.1055/s-0038-1672184. eCollection 2018 Jul.
Three-finger toxins (3FTxs) contribute to toxicity of venomous snakes belonging to the family Elapidae. Currently, functions of a considerable proportion of 3FTxs are still unknown. Here, we describe the function of orphan group I 3FTxs consisting of four members. We also identified a new member of this group by sequencing a transcript isolated from venom. This transcript, named najalexin, is identical to that previously described 3FTx from venom gland, and shared high sequence identity with ringhalexin from and a hypothetical protein from (here named as ophiolexin). The three-dimensional structure, as predicted by molecular modeling, showed that najalexin and ophiolexin share the same conserved structural organization as ringhalexin and other 3FTxs. Since ringhalexin inhibits the activation of factor X by the tissue factor-factor VIIa complex (TF-FVIIa), we evaluated the interaction of this group of 3FTxs with all components using protein-protein docking studies. The binding of orphan group I 3FTxs to TF-FVIIa complex appears to be driven by their interaction with TF. They bind to fibronectin domain closer to the 170-loop of the FVIIa heavy chain to inhibit factor X activation. The docking studies reveal that functional site residues Tyr7, Lys9, Glu12, Lys26, Arg34, Leu35, Arg40, Val55, Asp56, Cys57, Cys58, and Arg65 on these 3FTxs are crucial for interaction. replacement of these residues by Ala resulted in significant effects in the binding energies. Furthermore, these functional residues are not found in other groups of 3FTxs, which exhibit distinct pharmacological properties.
三指毒素（3FTxs）是眼镜蛇科毒蛇毒液毒性的组成部分。目前，相当一部分3FTxs的功能仍不清楚。在此，我们描述了由四个成员组成的孤儿I组3FTxs的功能。我们还通过对从毒液中分离的转录本进行测序，鉴定出了该组的一个新成员。这个转录本名为纳贾毒素，与先前描述的来自毒腺的3FTx相同，并且与来自[某种蛇]的环蛇毒素以及来自[某种蛇]的一个假设蛋白（此处命名为蛇毒素）具有高度的序列同一性。通过分子建模预测的三维结构表明，纳贾毒素和蛇毒素与环蛇毒素及其他3FTxs具有相同的保守结构组织。由于环蛇毒素可抑制组织因子 - 因子VIIa复合物（TF - FVIIa）对因子X的激活，我们使用蛋白质 - 蛋白质对接研究评估了这组3FTxs与所有组分的相互作用。孤儿I组3FTxs与TF - FVIIa复合物的结合似乎是由它们与TF的相互作用驱动的。它们与纤连蛋白结构域结合，靠近FVIIa重链的170 - 环，以抑制因子X的激活。对接研究表明，这些3FTxs上的功能位点残基Tyr7、Lys9、Glu12、Lys26、Arg34、Leu35、Arg40、Val55、Asp56、Cys57、Cys58和Arg65对于相互作用至关重要。用丙氨酸取代这些残基会对结合能产生显著影响。此外，这些功能残基在其他3FTxs组中未发现，而其他组表现出不同的药理特性。
