Mechanistic insights into fatty acid odor detection mediated by class II olfactory receptors

Smell is one of the fundamental senses mediated by thousands of odorant receptors (ORs). How hydrophobic and volatile odor molecules are recognized by class II ORs remains elusive. Here, we present cryo-electron microscopy (cryo-EM) structures of class II OR Olfr110 complexed with the unsaturated fatty acid metabolite (UFAM) PL45, Gs, and cons-OR5. The structural study revealed an unusually large hydrophobic pocket accommodating PL45 and the endogenous agonist 12(S)-hydroxyeicosapentaenoic acid (12(S)-HEPE). This pocket is decorated with polar residues and aromatic residue arrays, constituting polar networks and π-π interactions with the natural agonist PL45, respectively. Conserved motifs in the type II OR5 subfamily responsible for ligand recognition are characterized. The inward movement of extracellular loop 3 (ECL3) and an unconventional activation mechanism underlie Olfr110 activation. At the G protein interface, Olfr110 displays common and unique interactions. Overall, we revealed the structural basis of odor recognition and the activation mechanism of class II ORs, which may facilitate drug development targeting these receptors.