Understanding the molecular mechanisms of odorant binding and activation of the human OR52 family
Chulwon Choi, Jungnam Bae, Seonghan Kim, Seho Lee, Hyunook Kang, Jinuk Kim, Injin Bang, Ki-Heon Kim, Won‐Ki Huh, Chaok Seok, Hahnbeom Park, Wonpil Im, Hee‐Jung Choi
Abstract
Abstract Structural and mechanistic studies on human odorant receptors (ORs), key in olfactory signaling, are challenging because of their low surface expression in heterologous cells. The recent structure of OR51E2 bound to propionate provided molecular insight into odorant recognition, but the lack of an inactive OR structure limited understanding of the activation mechanism of ORs upon odorant binding. Here, we determined the cryo-electron microscopy structures of consensus OR52 (OR52 cs ), a representative of the OR52 family, in the ligand-free (apo) and octanoate-bound states. The apo structure of OR52 cs reveals a large opening between transmembrane helices (TMs) 5 and 6. A comparison between the apo and active structures of OR52 cs demonstrates the inward and outward movements of the extracellular and intracellular segments of TM6, respectively. These results, combined with molecular dynamics simulations and signaling assays, shed light on the molecular mechanisms of odorant binding and activation of the OR52 family.