芋螺毒素与钙离子通道相互作用的计算机模拟

Computational simulation of interaction between calcium channel and conotoxin

电压门控N-型钙离子通道是与神经元中释放的神经信号传递有关的跨细胞膜的特殊蛋白质分子。它由好几个蛋白质亚基组成,其中的α1亚基包含了电压敏感器和钙离子的选择性孔道。该亚基的一级结构已经发表,一般认为α1亚基包含4个重复单位(Ⅰ～Ⅳ),每个重复单位包括6段跨膜区(S1～S6)。其中跨膜区S4上有很多正电荷,被认为是通道的电压敏感器。S5和S6之间的连接区(P区)被认为是形成通道的门孔的部分。N-型钙离子通道能够被一些ω-芋螺毒素特异性地阻断,这些ω-芋螺毒素的三维结构已经由二维核磁共振方法测定。尽管还没有被证实,但一般认为ω-芋螺毒素占据了通道的孔道。有实验证明,钙离子第三个重复单位的P区(ⅢP区)是通道和芋螺毒素结合的主要部位。在本文中,我们用分子模拟程序模建了ⅢP区的结构。为了对通道的阻断机理有一个清楚的了解,我们利用分子对接程序模拟了ⅢP区和三种芋螺毒素GⅤA、MⅦA和SO3作用的理论模型。在我们的模型中,GⅥA与钙通道的作用方式可能与MⅦA不同,而MⅦA和SO3与钙通道的作用方式可能相同。我们还讨论了这些芋螺毒素中的关键残基的作用。

N-type voltage-gated calcium channels are membrane-bound proteins involved in neurotransmitter release from neurons.The channel consists of several protein subunits but it is the(1subunit which contains both voltage sensor and the Ca 2+ selective pore.The primary sequence of this subunit has been reported and has been proposed to consists of four repeated domains(I-IV),each of which is suggested to contain six transmembrane regions(S1-S6).The region S4is highly positively charged and is thought to form the voltage sensor.There is an additional region(P region)between S5and S6which is thought to form at least part of the pore region of the channel.N-type calcium channels are selectively blocked by a number of small peptide neurotoxin,theω-conotoxin.The three-di-mensional structures of several of these have been solved by2D NMR techniques.It is generally thought that these toxin occlude the pore,although this has not been proved.The P region of domain III(III P region)has been shown to be the principle binding region for conotoxin.In this paper,we construct the model of III P region using the graphic molecular modeling program.To gain a better understanding on the mechanism of the channel blockade,we present the plausible binding model ofω-conotoxin GVIA,MVIIA and SO3to III P region by using an auto-mated docking program.In our model,the interactions with calcium channel of GVIA and MVIIA maybe not identi-cal,but the interactions with calcium channel of MVIIA and SO3are probably similar.The role of the key residues of these conotoxins have been elucidated.