Research Article

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

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PNAS April 24, 2018 115 (17) E3950-E3958; first published April 9, 2018; https://doi.org/10.1073/pnas.1713026115

  1. Edited by Jerrold Meinwald, Cornell University, Ithaca, NY, and approved March 21, 2018 (received for review July 21, 2017)

Article Figures & SI

Figures

  • Fig. 1.
    Fig. 1.

    Three classes of musk compounds and related compounds used in this study.

  • Fig. 2.
    Fig. 2.

    Response of human musk receptors to various musk compounds. The response of the human musk receptors (A) OR5AN1 and (B) OR1A1 toward 12-, 13-, and 15- to 17-membered ring macrocyclic musks, nitromusks, and polycyclic musks. For all dose–response graphs, the y axis represents normalized luciferase activity ±SEM (n = 3). The responses of OR5AN1 are normalized to the highest value of racemic muscone 1, and the responses of OR1A1 to musk ambrette 22.

  • Fig. 3.
    Fig. 3.

    Fluorinated musk compounds used in this study.

  • Fig. 4.
    Fig. 4.

    Response of OR5AN1 to fluorinated (R)-muscone–related analogs. The responses are normalized to the highest value of (R)-muscone.

  • Fig. 5.
    Fig. 5.

    Side view of the homology model (A) OR5AN1 and (B) OR1A1 including seven-transmembrane α-helices (color key: TM1, blue; TM2, light blue; TM3, light green; TM4, green; TM5, yellow; TM6, orange; and TM7, red); the odorant (shown as space-filling models) binds at the periphery of the receptor, near the extracellular loop 2 ECL2, by H-bonding to Tyr260 in OR5AN1 and to Tyr258 in OR1A1. The circled region indicates the presence of the conserved DRY motif at sites Asp122, Arg123 and Tyr124 in OR5AN1. The magenta color stick represents the disulfide bond between Cys98 and Cys180 in OR5AN1 (A) and between Cys97 and Cys179 in OR1A1 (B). (C) Ligand–protein interactions of musk ketone with the polar (blue) and hydrophobic (green) residues, including the H-bonding interaction (dashed magenta lines) with Tyr260 are shown. (D) OR1A1 binds musk tibetene by H-bonds with Tyr258 in the binding site (one-letter amino acid codes used).

  • Fig. 6.
    Fig. 6.

    (A) Binding site of OR5AN1. The light purple color represents the extracellular loop (ECL2). (B) Musk ketone bound by H-bonding to Tyr260 (TM6) and one water molecule in the OR5AN1 as modeled by density functional theory QM/MM. Color code: orange, musk ketone; light blue,Tyr260; and dark blue, three phenylalanine residues (Phe105, Phe194, and Phe252) around 4.0 Å. (C) Binding site of OR1A1. (D) Musk tibetene bound by H-bonding to Tyr258 (blue, Tyr258). The hydrophobic residues around 4.0 Å (Ile105, Ile184, Tyr113, Ile205, Phe206, and Tyr251) are shown in light blue. The corresponding Ballesteros–Weinstein numberings are shown in the subscript.

  • Fig. 7.
    Fig. 7.

    Hydrophobic and aromatic residues that form the binding pocket of OR5AN1 with (A) and without (apo) (B) the odorant [cyclopentadecanol (3) in black stick]. Color key: hydrophobic residues (cyan) and Tyr260 (green).

  • Fig. 8.
    Fig. 8.

    Responses of human musk receptor active-site mutants to corresponding musk-smelling ligands. (A) Responses of OR5AN1 active-site mutants to macrocyclic musks (1, 2, 5, 8, 11, and 12), nitromusks (19–21), and fluorinated musks [(E)-34, (Z)-37]. (B) Responses of OR1A1 active-site mutants to nitromusks (20–22). Responses are normalized to responses of the wild-type receptor to each ligand.

  • Fig. 9.
    Fig. 9.

    Atom-based QSAR model. Experimental pEC50 vs. calculated pEC50 for the training and test sets.

Tables

  • Table 1.

    Calculated QM/MM binding energy profile of the musk odorants

    Odorant receptorOdorantsBinding energy, kcal/molEC50, μM
    OR5AN119−54.970.02
    20−54.081.28
    21−52.321.74
    12−50.773.43
    9−51.974.78
    11−51.135.23
    2−49.277.32
    3−50.569.05
    10−48.929.15
    5−50.0010.58
    (R)-1−48.4519.94
    (S)-1−47.06—
    8−46.7619.0
    28−53.624.63
    33−49.89*10.75
    29−48.0312.56
    (Z)-34−49.543.77
    (R,E)-34−52.910.03
    (S,E)-34−51.20—
    (R)-30−53.093.23
    (S)-30−51.15—
    35−52.71*0.27
    (E)-36−48.2914.07
    31−49.6111.20
    (E)-37−48.367.22
    (Z)-37−45.3823.33
    32−46.59*15.47
    (Z)-32−47.5517.25
    OR1A121−49.3916.67
    20−55.4415.71
    22−45.527.69

    • ↵* For QM/MM modeling, the (E)-conformer for 32 and 33 were used. For 35 we used the (Z)-conformer. The names and structures for the compounds can be found in Figs. 1 and 3.

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Molecular mechanism of activation of human musk receptors OR5AN1 and OR1A1 by (R)-muscone and diverse other musk-smelling compounds
Lucky Ahmed, Yuetian Zhang, Eric Block, Michael Buehl, Michael J. Corr, Rodrigo A. Cormanich, Sivaji Gundala, Hiroaki Matsunami, David O’Hagan, Mehmet Ozbil, Yi Pan, Sivakumar Sekharan, Nicholas Ten, Mingan Wang, Mingyan Yang, Qingzhi Zhang, Ruina Zhang, Victor S. Batista, Hanyi Zhuang
Proceedings of the National Academy of Sciences Apr 2018, 115 (17) E3950-E3958; DOI: 10.1073/pnas.1713026115
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  • Biological Sciences
  • Biophysics and Computational Biology
Proceedings of the National Academy of Sciences: 115 (17)
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