Deciphering olfactory receptor binding mechanisms: a structural and dynamic perspective on olfactory receptors

Abstract

Olfactory receptors, classified as G-protein coupled receptors (GPCRs), have been a subject of scientific inquiry since the early 1950s. Historically, investigations into the sensory mechanisms of olfactory receptors were often confined to behavioral characteristics in model organisms or the expression of related proteins and genes. However, with the development of cryo-electron microscopy techniques, it has gradually become possible to decipher the specific structures of olfactory receptors in insects and humans. This has provided new insights into the binding mechanisms between odor molecules and olfactory receptors. Furthermore, due to the rapid advancements in related fields such as computer simulations, the prediction and exploration of odor molecule binding to olfactory receptors have been progressively achieved through molecular dynamics simulations. Through this comprehensive review, we aim to provide a thorough analysis of research related to the binding mechanisms between odor molecules and olfactory receptors from the perspectives of structural biology and molecular dynamics simulations. Finally, we will provide an outlook on the future of research in the field of olfactory receptor sensory mechanisms.

Keywords: molecular dynamics simulations; odor molecules; olfactory receptors; sensory mechanisms; structural biology.

FIGURE 1

Significant research breakthroughs in olfactory receptors from 2004 to 2024. (A) The Nobel Prize in Physiology or Medicine (Buck and Axel, 1991); (B) Mice have special olfactory neurons that can sense carbon dioxide in the air (Hu et al., 2007); (C) Protein-Mediated Odor Recognition in Mosquitoes and Drosophila melanogaster (Wang and Anderson, 2009); (D) Asymmetric Neurotransmitter Release Facilitates Rapid Odor Recognition in Fruit Flies (Gaudry et al., 2012); (E) Through computational simulations, the study elucidates how olfactory neurons achieve monoallelic expression of olfactory receptors while maintaining diversity in their expression (Tian et al., 2016); (F) Structural Analysis of the Insect Olfactory Receptor Orco Using Cryo-Electron Microscopy (Butterwick et al., 2018); (G) The LDB1 Protein Governs the Expression of Olfactory Genes (Monahan et al., 2019); (H) Structural Analysis of the OR5 Receptor and Odor Molecule Binding Mechanisms in Machilis hrabei (Del Mármol et al., 2021); (I) The study elucidates the evolutionary origins, history, and co-evolutionary process of ligand recognition for a family of olfactory receptors known as trace amine-associated receptors (Guo et al., 2022); (J) The Inaugural Precision Three-Dimensional Structural Mapping of the Human Odor Receptor (OR51E2) Has Been Accomplished (Billesbolle et al., 2023).

FIGURE 2

Schematic diagram of GPCR protein structure. (A) Main view of GPCR protein, with arrows indicating the seven transmembrane regions. (B) Top view of GPCR protein, with arrows pointing to three extracellular loops. (C) Bottom view of GPCR protein, with arrows pointing to three intracellular loops. (D) Plan view of GPCR protein structure.

FIGURE 3

Methods for Studying the Olfactory Receptor - Odorant Binding Mechanism. (A) Resolving protein structures through cryo-electron microscopy (Cryo-EM) or predicting protein conformations using AlphaFold2. (B) Using molecular docking and molecular dynamics simulations to bind odorants with olfactory receptors. (C) Analyzing the interactions forces between protein and ligand. (D) Identifying crucial amino acid residues, inducing mutations, molecular docking and molecular dynamics simulations, and further analyzing the binding mechanism. (E) Cellular experiments are conducted to detect the activation of olfactory receptors, validating the proposed mechanism.