Identification Of Entry Pathway And Binding Site Of Insect Odorant Co-Receptor

Abstract

Insects are of major importance for our society, either benefit for agriculture or detrimental for human health as pathogen vectors. Olfaction is an essential sense for insects notably for food and host seeking. The insect odorant receptors are cationic channels, contrary to their mammal counterpart that are metabotropic receptors. Recent progress in the atomic resolution of their structures offers unprecedented opportunities for deciphering their molecular mechanisms and particularly the binding mode of their ligands. Odorants bind to the odorant receptor (OR) subunits, while the second mandatory subunit so called odorant receptor co-receptor (ORco) binds chemicals like VUAA1. Despite groundbreaking studies in insect olfaction, many questions are still not answered and most elementary functional characteristics of insect ORco remain to be defined. In particular, little is known about the binding site and entry pathway of VUAA1 and derivatives into ORco. Their identification is essential for both a better understanding of the specificity of action of VUAA1-based molecules and structural insights for the rational design of new ORco ligands. In this study, we focus our work on the molecular features of the receptor protein that determine the ligand specificity and the molecular processes that contribute to the striking sensitivity of the insect olfactory system. We therefore combined results from molecular modeling with site-directed mutagenesis and two electrodes voltage clamp (TEVC) measurement to identify both the binding pocket and the translocation pathway of VUAA1 from the extracellular space to the binding site.