Diverse yet selective tuning of an odorant receptor for sensing four classes of musk compounds

Abstract Musk was originally identified in male musk deer and other mammals to mark territories and attract females. In humans, musk compounds are widely used in perfumes and consumer products for their superior perceptual odor quality. Strikingly diverse natural and synthetic chemicals have similar “musky” odor, which has resulted in diverse models of musk odor perception and has raised questions regarding simplistic associations between chemical features and odor quality. Scientists’ lack of understanding of this principle has hampered the design of a novel musk compound. Here, we functionally identified the odorant receptor, OR5A2, as a receptor for the musky odor of diverse musk compounds. First, we discovered that engineered OR5A2 with enhanced expression in heterologous cells is sensitive and selective to musk compounds in all four structural classes. Second, the clarified functional variation of OR5A2 accounts for the reported association between genetic variation and perception in a musk compound. Finally, the revealed ligand selectivity of OR5A2 provides insight into developing a trained model for machine learning-based virtual screening of candidates for a new musk compound. We propose that OR5A2 contributes to the long-sought gateway for sensing musk compounds and generating its unique odor quality.