Abstact

Mammalian odorant receptors (ORs) sense diverse environmental chemicals, yet structural insights into odorant recognition by mammalian class II ORs remain limited. Here, we present the cryo-EM structure of a native mammalian class II OR, mouse Olfr412, a human OR1D2 ortholog, bound to the odorant methyl-trans-cinnamate and the G(s) protein. The odorant-binding pocket of Olfr412 is located deeper within the transmembrane domain than that of the class I OR OR51E2 and is largely composed of poorly conserved hydrophobic residues, providing a structural basis for broad odorant recognition in class II ORs. Structural and molecular dynamics analyses suggest that the conserved Y(6x55) plays a key role in odorant recognition and activation, functionally paralleling R(6x59) in class I ORs and is further stabilized by intramolecular interaction with the conserved ECL2 residue E(45x51). Together, our findings uncover structural mechanisms underlying odorant recognition and activation in class II ORs.