Mahdavi Somayeh, Kuyucak Serdar
School of Physics, University of Sydney, Sydney, New South Wales 2006, Australia.
Toxins (Basel). 2014 Dec 18;6(12):3454-70. doi: 10.3390/toxins6123454.
Voltage-gated sodium channels (NaV) are fundamental components of the nervous system. Their dysfunction is implicated in a number of neurological disorders, such as chronic pain, making them potential targets for the treatment of such disorders. The prominence of the NaV channels in the nervous system has been exploited by venomous animals for preying purposes, which have developed toxins that can block the NaV channels, thereby disabling their function. Because of their potency, such toxins could provide drug leads for the treatment of neurological disorders associated with NaV channels. However, most toxins lack selectivity for a given target NaV channel, and improving their selectivity profile among the NaV1 isoforms is essential for their development as drug leads. Computational methods will be very useful in the solution of such design problems, provided accurate models of the protein-ligand complex can be constructed. Using docking and molecular dynamics simulations, we have recently constructed a model for the NaV1.4-μ-conotoxin-GIIIA complex and validated it with the ample mutational data available for this complex. Here, we use the validated NaV1.4 model in a systematic study of binding other μ-conotoxins (PIIIA, KIIIA and BuIIIB) to NaV1.4. The binding mode obtained for each complex is shown to be consistent with the available mutation data and binding constants. We compare the binding modes of PIIIA, KIIIA and BuIIIB to that of GIIIA and point out the similarities and differences among them. The detailed information about NaV1.4-μ-conotoxin interactions provided here will be useful in the design of new NaV channel blocking peptides.
电压门控钠通道（NaV）是神经系统的基本组成部分。它们的功能障碍与多种神经系统疾病有关，如慢性疼痛，这使它们成为治疗此类疾病的潜在靶点。有毒动物利用神经系统中NaV通道的突出地位进行捕食，它们进化出了能够阻断NaV通道的毒素，从而使其功能丧失。由于这些毒素的效力，它们可为治疗与NaV通道相关的神经系统疾病提供药物先导。然而，大多数毒素对特定的目标NaV通道缺乏选择性，提高它们在NaV1亚型中的选择性对于将其开发为药物先导至关重要。如果能够构建准确的蛋白质-配体复合物模型，计算方法将在解决此类设计问题中非常有用。利用对接和分子动力学模拟，我们最近构建了NaV1.4-μ-芋螺毒素-GIIIA复合物的模型，并利用该复合物大量的突变数据对其进行了验证。在此，我们使用经过验证的NaV1.4模型系统地研究其他μ-芋螺毒素（PIIIA、KIIIA和BuIIIB）与NaV1.4的结合。每个复合物获得的结合模式与可用的突变数据和结合常数一致。我们将PIIIA、KIIIA和BuIIIB的结合模式与GIIIA的结合模式进行比较，并指出它们之间的异同。本文提供的关于NaV1.4-μ-芋螺毒素相互作用的详细信息将有助于设计新的NaV通道阻断肽。
