Dissecting the molecular mechanism of drosophila odorant receptors through activity modeling and comparative analysis.

To gain insight into the molecular mechanism of odorant receptors (ORs) in Drosophila species, we developed a Quantitative Structure Activity Relationship (QSAR) model that predicts experimentally measured electrophysiological activities between 24 D. melanogaster ORs and 108 odorants. Although the model is limited by the tested odorants,analyzing the model allowed dissection of specific topological and chemical properties necessary for an odorant to elicit excitatory or inhibitory receptor response. Linear odorants with five to eight nonhydrogen atoms at the main chain and hydrogen-bond acceptor and/or hydrogen-bond donor at its ends were found to stimulate strong excitatory response. A comparative sequence analysis of 90 ORs in 15 orthologous groups identified 15 putative specificity-determining residues (SDRs) and 15 globally conserved residues that we postulate as functionally key residues. Mapping to a model of secondary structure resulted in 14 out of 30 key residues locating to the transmembrane (TM) domains. Twelve residues, including six SDRs and six conserved residues, are located at the extracellular halves of the TM domains. Combining the evidence from the QSAR modeling and the comparative sequence analysis, we hypothesize that the Drosophila ORs accept odorants into a binding pocket located on the extracellular halves of its TM domains. The QSAR modeling suggests that the binding pocket is around 15 A in depth and about 6 A in width. Twelve mainly polar or charged key residues, both SDRs and conserved, are located in this pocket and postulated to distinguish docked odorants via primarily geometry fitting and hydrogen-bond interaction.