Structural dynamics of human odorant receptors in olfaction

PROJECT SUMMARY Our sense of smell depends on our ability to detect and discriminate a vast array of odor molecules. In vertebrates, odors are predominantly detected by odorant receptors (ORs), which are G protein-coupled receptors (GPCRs) in vertebrates. The human genome encodes ~400 ORs, providing our olfactory system with the ability to detect diverse odorants. Despite incredible advances in our understanding of GPCR function, the fundamental molecular logic of odorant recognition by ORs remains elusive. It is unclear why closely related ORs can have distinct odorant preferences, or why some ORs respond to a small subset of odorants while others are more broadly responsive. Moreover, the process by which an odorant turns an OR “on” is not well understood. Recently, our collaborative team determined the first experimental structure of a vertebrate OR, the human receptor OR51E2, which provided critical insights into molecular recognition and OR activation. Building on this advance, we will address three fundamental aspects of odorant receptor biology: 1) Identify OR features that are responsible for odorant selectivity, 2) Reveal distinctions in odorant recognition by Class I and Class II ORs, and 3) Describe the fundamental mechanisms for how odorants activate ORs. Towards this end, we will combine structure determination with iterative mutagenesis studies and molecular dynamics simulations, thereby providing direct insight into the molecular logic of odorant recognition and OR activation. The proposed studies will provide fundamental insights into the structure and dynamics of OR function and yield inroads into an atomic framework for understanding our sense of smell.