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; Kiheon Kim; Won Ki Huh; Chaok Seok; Hahnbeom Park; Wonpil Im; Hee Jung Choi

doi:10.1038/s41467-023-43983-9

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
, Kiheon Kim
, Won Ki Huh
, Chaok Seok
, Hahnbeom Park
, Wonpil Im
, Hee Jung Choi

Research output: Contribution to journal › Article › peer-review

39 Scopus citations

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.

Original language	English
Article number	8105
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-43983-9
State	Published - Dec 2023
Externally published	Yes

Funding

We thank Dr. Matsunami (Duke University) for kindly providing Hana3A cells. This work was supported by Samsung Science and Technology Foundation under Project Number SSTF-BA1901-09 (to H.-J.C.), and National Science Foundation, USA (MCB-2111728 to W.I.). We thank our research assistant, Bo Ram Seo, for her experimental support. We also thank Dr. Bum Han Ryu (Institute for Basic Science (IBS), Korea) and Dr. Su Jeong Kim (Institute of Membrane Proteins (IMP), Postech, Korea) for supporting data collection at IBS and IMP cryo-EM facilities, respectively, and Global Science experimental Data hub Center (GSDC) and KREONET at Korea Institute of Science and Technology Information (KISTI) and the data analysis hub, Olaf at the IBS Research Solution Center for computing resources. Anton 2 computer time was provided by PSC through Grant R01GM116961 from the National Institutes of Health. The Anton 2 machine at PSC was generously made available by D.E. Shaw Research.

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title = "Understanding the molecular mechanisms of odorant binding and activation of the human OR52 family",

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 (OR52cs), a representative of the OR52 family, in the ligand-free (apo) and octanoate-bound states. The apo structure of OR52cs reveals a large opening between transmembrane helices (TMs) 5 and 6. A comparison between the apo and active structures of OR52cs 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.",

author = "Chulwon Choi and Jungnam Bae and Seonghan Kim and Seho Lee and Hyunook Kang and Jinuk Kim and Injin Bang and Kiheon Kim and Huh, \{Won Ki\} and Chaok Seok and Hahnbeom Park and Wonpil Im and Choi, \{Hee Jung\}",

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AU - Choi, Chulwon

AU - Bae, Jungnam

AU - Kim, Seonghan

AU - Lee, Seho

AU - Kang, Hyunook

AU - Kim, Jinuk

AU - Bang, Injin

AU - Kim, Kiheon

AU - Huh, Won Ki

AU - Seok, Chaok

AU - Park, Hahnbeom

AU - Im, Wonpil

AU - Choi, Hee Jung

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Y1 - 2023/12

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AB - 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 (OR52cs), a representative of the OR52 family, in the ligand-free (apo) and octanoate-bound states. The apo structure of OR52cs reveals a large opening between transmembrane helices (TMs) 5 and 6. A comparison between the apo and active structures of OR52cs 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.

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Understanding the molecular mechanisms of odorant binding and activation of the human OR52 family

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