Modelling insecticide-binding sites in the voltage-gated sodium channel.
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.
Department of Crystallography, Birkbeck College, University of London, London WC1E 7HX, United Kingdom.
Andrias O
AO
O'Reilly
Bhupinder P S
BP
Khambay
Martin S
MS
Williamson
Linda M
LM
Field
B A
BA
Wallace
T G Emyr
TG
Davies
D000595:Amino Acid Sequence; D000818:Animals; D001097:Arachnida / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D003634:DDT / Q000378:metabolism / Q000494:pharmacology; D006793:Houseflies / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007305:Insecticide Resistance / Q000187:drug effects / Q000235:genetics; D007306:Insecticides / Q000378:metabolism* / Q000494:pharmacology; D051663:Kv1.2 Potassium Channel / Q000737:chemistry / Q000235:genetics; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009570:Nitriles / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation / Q000187:drug effects; D011722:Pyrethrins / Q000378:metabolism / Q000494:pharmacology; D016415:Sequence Alignment; D015222:Sodium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
D007306:Insecticides; D051663:Kv1.2 Potassium Channel; D008024:Ligands; D009570:Nitriles; D011722:Pyrethrins; D015222:Sodium Channels; D003634:DDT; C017690:fenvalerate