Molecular mechanism of activation of human musk receptors OR5AN1 and OR1A1 by (R)-muscone and diverse other musk-smelling compounds

Ahmed, Lucky; Zhang, Yuetian; Block, Eric; Buehl, Michael; Corr, Michael J.; Cormanich, Rodrigo A.; Gundala, Sivaji; Matsunami, Hiroaki; O’Hagan, David; Ozbil, Mehmet; Pan, Yi; Sekharan, Sivakumar; Ten, Nicholas; Wang, Mingan; Yang, Mingyan; Zhang, Qingzhi; Zhang, Ruina; Batista, Victor S.; Zhuang, Hanyi

doi:10.1073/pnas.1713026115

Title: Molecular mechanism of activation of human musk receptors OR5AN1 and OR1A1 by (R)-muscone and diverse other musk-smelling compounds

Journal Article · Mon Apr 09 00:00:00 EDT 2018 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1713026115· OSTI ID:1543905

^[1]; Zhang, Yuetian ^[2];

^[3]; Buehl, Michael ^[4]; Corr, Michael J. ^[4]; Cormanich, Rodrigo A. ^[5]; Gundala, Sivaji ^[3]; Matsunami, Hiroaki ^[6]; O’Hagan, David ^[4]; Ozbil, Mehmet ^[1]; Pan, Yi ^[2]; Sekharan, Sivakumar ^[1]; Ten, Nicholas ^[1]; Wang, Mingan ^[7]; Yang, Mingyan ^[8]; Zhang, Qingzhi ^[4]; Zhang, Ruina ^[2]; Batista, Victor S. ^[1]; Zhuang, Hanyi ^[9]

Yale Univ., New Haven, CT (United States)
Shanghai Jiao Tong Univ. School of Medicine, Shanghai (People’s Republic of China)
Univ. at Albany, State Univ. of New York, Albany, NY (United States)
Univ. of St. Andrews, St. Andrews (Scotland)
Univ. of Campinas, Campinas (Brazil)
Duke Univ. Medical Center, Durham, NC (United States)
China Agricultural Univ., Beijing (People's Republic of China)
Univ. of St. Andrews, St. Andrews (Scotland); China Agricultural Univ., Beijing (People's Republic of China)
Shanghai Jiao Tong Univ. School of Medicine, Shanghai (People’s Republic of China); Chinese Academy of Sciences, Shanghai (People's Republic of China)

Understanding olfaction at the molecular level is challenging due to the lack of crystallographic models of odorant receptors (ORs). To better understand the molecular mechanism of OR activation, we focused on chiral (R)-muscone and other musk-smelling odorants due to their great importance and widespread use in perfumery and traditional medicine, as well as environmental concerns associated with bioaccumulation of musks with estrogenic/antiestrogenic properties. We experimentally and computationally examined the activation of human receptors OR5AN1 and OR1A1, recently identified as specifically responding to musk compounds. OR5AN1 responds at nanomolar concentrations to musk ketone and robustly to macrocyclic sulfoxides and fluorine-substituted macrocyclic ketones; OR1A1 responds only to nitromusks. Structural models of OR5AN1 and OR1A1 based on quantum mechanics/molecular mechanics (QM/MM) hybrid methods were validated through direct comparisons with activation profiles from site-directed mutagenesis experiments and analysis of binding energies for 35 musk-related odorants. The experimentally found chiral selectivity of OR5AN1 to (R)- over (S)-muscone was also computationally confirmed for muscone and fluorinated (R)-muscone analogs. Structural models show that OR5AN1, highly responsive to nitromusks over macrocyclic musks, stabilizes odorants by hydrogen bonding to Tyr260 of transmembrane α-helix 6 and hydrophobic interactions with surrounding aromatic residues Phe105, Phe194, and Phe207. As a result, the binding of OR1A1 to nitromusks is stabilized by hydrogen bonding to Tyr258 along with hydrophobic interactions with surrounding aromatic residues Tyr251 and Phe206. Hydrophobic/nonpolar and hydrogen bonding interactions contribute, respectively, 77% and 13% to the odorant binding affinities, as shown by an atom-based quantitative structure–activity relationship model.

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Research Organization:: Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)

Sponsoring Organization:: USDOE

OSTI ID:: 1543905

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, Issue 17; ISSN 0027-8424

Publisher:: National Academy of Sciences, Washington, DC (United States)Copyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 40 works

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Copper-mediated thiol potentiation and mutagenesis-guided modeling suggest a highly conserved copper-binding motif in human OR2M3 Haag, Franziska; Ahmed, Lucky; Reiss, Krystle Cellular and Molecular Life Sciences, Vol. 77, Issue 11 https://doi.org/10.1007/s00018-019-03279-y	journal	August 2019
Beyond the Flavour: The Potential Druggability of Chemosensory G Protein-Coupled Receptors Di Pizio, Antonella; Behrens, Maik; Krautwurst, Dietmar International Journal of Molecular Sciences, Vol. 20, Issue 6 https://doi.org/10.3390/ijms20061402	journal	March 2019

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