Abstract
It is generally recognized that insect odorant binding proteins (OBPs) mediate the solubilisation and transport of hydrophobic odorant molecules and contribute to the sensitivity of the insect olfactory system. However, the exact mechanism by which OBPs deliver odorants to olfactory receptors and their role, if any, as selectivity filters for specific odorants, are still a matter of debate. In the case of Anopheles gambiae, recent studies indicate that ligand discrimination is effected through the formation of heterodimers such as AgamOBP1 and AgamOBP4 (odorant binding proteins 1 and 4 from Anopheles gambiae). Furthermore, AgamOBPs have been reported to be promiscuous in binding more than one ligand simultaneously and repellents such as DEET (N,N-diethyl-3-toluamide) and 6-MH (6-methyl-5-hepten-2-one) interact directly with mosquito OBPs and/or compete for the binding of attractive odorants thus disrupting OBP heterodimerisation. In this paper, we propose mechanisms of action of DEET and 6-MH. We also predict that ligand binding can occur in several locations of AgamOBP1 with partial occupancies and propose structural features appropriate for repellent pharmacophores.
Highlights
Mosquitoes occupy the leading place among insect vectors responsible for the transmission of parasitic and viral infections, such as malaria, yellow fever, dengue and Chikungunya
We present molecular dynamics (MD) simulations of AgamOBP1 in complex with 6-MH and DEET to determine (a) whether simultaneous binding of two ligands brings about conformational transitions; (b) the effect, if any, of ligand binding on AgamOBP1 dimerisation, and (c) possible AgamOBP1 binding sub-sites that could be explored in the design of better analogues for ligand binding
The starting coordinates for the MD simulations were taken from the X-ray structures of AgamOBP1-DEET (PDB ID: 3N7H) and AgamOBP1-6MH (PDB ID: 4FQT) and unliganded AgamOBP1 (PDB ID: 3N7H)
Summary
Mosquitoes occupy the leading place among insect vectors responsible for the transmission of parasitic and viral infections, such as malaria, yellow fever, dengue and Chikungunya. Preventive and/or therapeutic interventions against malaria have been frustrated either by the limited efficacy of malaria vaccines [2] or the emergence of resistance to modern drugs such as artemisin [3]. In view of these problems, alternative biotechnological approaches aimed at reducing contact between mosquitoes and human hosts are being considered. One such approach entails the disruption of the olfactory behaviour of the insect vectors. Interactions between odorant molecules and ORs are translated into ion gradient potential signals by transductory proteins
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