Structural highlights
Publication Abstract from PubMedThe Anopheles gambiae mosquito, which is the vector for Plasmodium falciparum malaria, uses a series of olfactory cues emanating from human sweat to select humans as their source for a blood meal. Perception of these odors within the mosquito olfactory system involves the interplay of odorant binding proteins (OBPs) and odorant receptors. Disrupting the normal responses to those odorants that guide mosquito-human interactions represents an attractive approach to prevent the transmission of malaria. Previously it has been shown that DEET targets multiple components of the olfactory system, including OPBs and odorant receptors. Here we present the crystal structure of Anopheles gambiae OBP1 (OBP1) in the complex it forms with a natural repellent 6-methyl-5-heptene-2-one (6-MH). We find that 6-MH binds to OBP1 at the same site as DEET. However, key interactions with a highly conserved water molecule that are proposed to be important for DEET binding are not involved in binding of 6-MH. We show that 6-MH and DEET can compete for the binding of attractive odorants and in doing so disrupt the interaction that OBP1 makes with OBP4. We further show that 6-MH and DEET can bind simultaneously to OBPs with other ligands. These results suggest that the successful discovery of novel reagents targeting OBP function requires knowledge about the specific mechanism of binding to the OBP rather than their binding affinity. Interactions of Anopheles gambiae odorant binding proteins with a human-derived repellent: implications for the mode of action of DEET.,Murphy EJ, Booth JC, Davrazou F, Port AM, Jones DN J Biol Chem. 2012 Dec 23. PMID:23261834[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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