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

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

  • Proc Natl Acad Sci U S A. 2018 Apr 24;115(17):E3950-E3958. doi: 10.1073/pnas.1713026115.
Lucky Ahmed 1,  Yuetian Zhang 2,  Eric Block 3,  Michael Buehl 4,  Michael J Corr 4,  Rodrigo A Cormanich 5,  Sivaji Gundala 6,  Hiroaki Matsunami 7 8,  David O'Hagan 9,  Mehmet Ozbil 1,  Yi Pan 2,  Sivakumar Sekharan 1,  Nicholas Ten 1,  Mingan Wang 10,  Mingyan Yang 4 10,  Qingzhi Zhang 4,  Ruina Zhang 2,  Victor S Batista 11,  Hanyi Zhuang 12 13
Affiliations

Affiliations

  • 1 Department of Chemistry, Yale University, New Haven, CT 06520.
  • 2 Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, People's Republic of China.
  • 3 Department of Chemistry, University at Albany, State University of New York, Albany, NY 12222; [email protected] [email protected] [email protected] [email protected].
  • 4 School of Chemistry, University of St. Andrews, North Haugh, KY16 9ST St. Andrews, Scotland.
  • 5 Department of Organic Chemistry, Chemistry Institute, University of Campinas, Campinas, SP 13083-970, Brazil.
  • 6 Department of Chemistry, University at Albany, State University of New York, Albany, NY 12222.
  • 7 Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710.
  • 8 Department of Neurobiology, Duke Institute for Brain Sciences, Duke University Medical Center, Durham, NC 27710.
  • 9 School of Chemistry, University of St. Andrews, North Haugh, KY16 9ST St. Andrews, Scotland; [email protected] [email protected] [email protected] [email protected].
  • 10 Department of Applied Chemistry, College of Science, China Agricultural University, Haidian District, 100193 Beijing, People's Republic of China.
  • 11 Department of Chemistry, Yale University, New Haven, CT 06520; [email protected] [email protected] [email protected] [email protected].
  • 12 Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, People's Republic of China; [email protected] [email protected] [email protected] [email protected].
  • 13 Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine/Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences, 200031 Shanghai, People's Republic of China.
PMID: 29632183 DOI: 10.1073/pnas.1713026115
Abstract

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. 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.

Keywords

molecular dynamics; musk; odorant receptor; olfaction; quantum mechanics.

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