Modelling insecticide-binding sites in the voltage-gated sodium channel
Modelling insecticide-binding sites in the voltage-gated sodium channel
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DOI：
10.1042/bj20051925
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发表时间：
2006-06-01
影响因子：
4.1
通讯作者：
Davies, T. G. Emyr
中科院分区：
文献类型：
--
作者：
O'Reilly, Andrias O.;Khambay, Bhupinder P. S.;Davies, T. G. Emyr
建立了家蝇电压门控钠通道的同源模型，用于预测杀虫剂氰戊菊酯（一种合成拟除虫菊酯）和DDT（一种早期有机氯）的结合位点。该模型成功地解决了状态依赖的拟除虫菊酯类杀虫剂的亲和力，其作用机制和已知赋予杀虫剂抗性的通道中的突变的作用。钠通道以开放构象建模，其中去磷酸化结合位点位于由结构域II S4-S5接头和IIS 5和IIIS 6螺旋界定的疏水腔中。结合腔被预测为可访问的脂双层，因此脂溶性杀虫剂。杀虫剂的结合和随后形成的跨不同通道元件的结合接触可以在开放状态下稳定通道，这与拟除虫菊酯和DDT诱导的延长的钠尾电流一致。在闭合状态下，结构域II S4-S5接头的预测替代定位将导致拟除虫菊酯结合接触的破坏，这与拟除虫菊酯对开放通道具有最高亲和力的观察结果一致。该模型还预测了一个关键作用的IIS 5和IIIS 6螺旋杀虫剂结合。螺旋上的一些残基，形成推定的结合接触是不保守的节肢动物和非节肢动物物种，这是一致的，他们的贡献杀虫剂物种的选择性。II S4-S5接头上的额外结合接触可以解释拟除虫菊酯杀虫剂与DDT相比具有更高的效力。
A homology model of the housefly voltage-gated sodium channel was developed to predict the location of binding sites for the insecticides fenvalerate, a synthetic pyrethroid, and DDT an early generation organochlorine. The model successfully addresses the state-dependent affinity of pyrethroid insecticides, their mechanism of action and the role of mutations in the channel that are known to confer insecticide resistance. The sodium channel was modelled in an open conformation with the insecticide-binding site located in a hydrophobic cavity delimited by the domain II S4-S5 linker and the IIS5 and IIIS6 helices. The binding cavity is predicted to be accessible to the lipid bilayer and therefore to lipid-soluble insecticides. The binding of insecticides and the consequent formation of binding contacts across different channel elements could stabilize the channel when in an open state, which is consistent with the prolonged sodium tail currents induced by pyrethroids, and DDT. In the closed state, the predicted alternative positioning of the domain II S4-S5 linker would result in disruption of pyrethroid-binding contacts, consistent with the observation that pyrethroids have their highest affinity for the open channel. The model also predicts a key role for the IIS5 and IIIS6 helices in insecticide binding. Some of the residues on the helices that form the putative binding contacts are not conserved between arthropod and non-arthropod species, which is consistent with their contribution to insecticide species selectivity. Additional binding contacts on the II S4-S5 linker can explain the higher potency of pyrethroid insecticides compared with DDT.