Insecticide binding to voltage-gated sodium channels
O’Reilly, Andrias O. and Davies, T.G.E. and Usherwood, P.N.R. and Mellor, I. and Williamson, M.S. and Field, L.M. and Wallace, Bonnie A. (2009) Insecticide binding to voltage-gated sodium channels. Biophysical Journal 96 (3(S1)), 14a-14a. ISSN 0006-3495.
DDT and the pyrethroid class of insecticides target voltage-gated sodium channels. Their binding stabilises the channel open state, inducing prolonged tail currents associated with insect paralysis (‘knockdown’) and death. Target-site mutations conferring resistance, while a challenge for pest control programs, have provided valuable information on the location of the elusive insecticide-binding site. Homology modelling of the housefly sodium channel and automated ligand docking studies have identified a binding site consistent with resistance-associated mutagenesis data, structure-activity relationships of insecticides and their state-dependent binding activity [O'Reilly et al (2006) Biochem. J. 396:255-263]. The putative binding site, delimited by the domain II S4-S5 linker, S5 & S6 helices and domain III S6 helix, interfaces the lipid bilayer and is therefore accessible to lipid-soluble insecticide ligands. The model is supported by recent experimental results from voltage-clamp electrophysiology studies on mutant fruitfly sodium channels [Usherwood et al (2007) FEBS Letters 581:5485-5492]. The mutation T929I, predicted to inhibit DDT binding through steric hindrance, abolishes the effects of DDT on channel activity. M918, a residue predicted to form a binding contact with pyrethroids but not DDT, decreased deltamethrin potency without effecting DDT potency when mutated. We have developed methods based on circular dichroism spectroscopy to identify ligand binding to a non-insect channel system, namely the voltage-gated sodium channel NaChBac from Bacillus halodurans [Nurani et al (2008) Biochemistry 31:8114-8121], which will be used as a further test of the binding of various insecticides as predicted by the model. (Supported by grants from the BBSRC)
|School:||Birkbeck Schools and Departments > School of Science > Biological Sciences|
|Research Centre:||Bioinformatics, Bloomsbury Centre for, Structural Molecular Biology, Institute of (ISMB)|
|Date Deposited:||04 Aug 2010 14:09|
|Last Modified:||07 Dec 2016 15:05|
Additional statistics are available via IRStats2.