Molecular determinants of olfactory receptor activation: Comparative analysis of Olfr205 and Olfr740 family member responses to indole

Abstract

Indole is widely present in nature and contributes significantly to the smell of flowers and animal excretion. However, the odor perception mechanism for indole is unclear, despite previous reports suggesting that it activates the Olfr740 family of receptors. In this study, we successfully identified another receptor, Olfr205, that is responsive to indole. Molecular model construction and binding pocket analysis predicted that the A202 residue in transmembrane helix 5 of Olfr205 forms a crucial hydrogen bond with indole, facilitating receptor activation. Additionally, G112 in transmembrane helix 3 of the Olfr740 family is involved in indole activation of receptors. Finally, our mutant function assay showed that substitution of A202 in Olfr205 and G112 in Olfr740 with other amino acids significantly decreased the receptor response to indole, which provides robust evidence to confirm the docking results. In summary, our study is the first to reveal that Olfr205 is an olfactory receptor distinct from those in the Olfr740 family that is activated by indole. Moreover, these receptors display different indole-binding mechanisms. This study sheds light on molecular binding mechanisms and contributes to a deeper understanding of indole perception.