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

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Date
24/04/2018
Author
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
Zhuang, Hanyi
Funder
EPSRC
Grant ID
EP/K022946/1
Keywords
Olfaction
Odorant receptor
Musk
Quantum mechanics
Molecular dynamics
QD Chemistry
QC Physics
NDAS
BDC
R2C
SDG 3 - Good Health and Well-being
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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 a-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.
Citation
Ahmed , L , Zhang , Y , Block , E , Buehl , M , Corr , M J , Cormanich , R A , Gundala , S , Matsunami , H , O'Hagan , D , Ozbil , M , Pan , Y , Sekharan , S , Ten , N , Wang , M , Yang , M , Zhang , Q , Zhang , R , Batista , V & Zhuang , H 2018 , ' Molecular mechanism of activation of human musk receptors OR5AN1 and OR1A1 by ( R )-muscone and diverse other musk-smelling compounds ' , Proceedings of the National Academy of Sciences of the United States of America , vol. 115 , no. 17 , pp. E3950-E3958 . https://doi.org/10.1073/pnas.1713026115
Publication
Proceedings of the National Academy of Sciences of the United States of America
Status
Peer reviewed
DOI
https://doi.org/10.1073/pnas.1713026115
ISSN
0027-8424
Type
Journal article
Rights
© 2018 the Author(s). This work has been made available online in accordance with the publisher’s policies. This is the author created, accepted version manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at https://doi.org/10.1073/pnas.1713026115
Description
We acknowledge support from NSF (CHE-1265679) and NIH (5R01DC014423 subaward) (EB), NIH (5R01 DC014423) (HM), the European Reasearch Council (ERC) and the Engineering Science Research Council (EPSRC) (DO'H), FAPESP and CNPq (RAC), the Chinese Scholarship Council (CSC) for studentship support (MY), National Science Foundation (31070972) (HZ), Science and Technology Commission of Shanghai Municipality (16ZR1418300) (HZ), the Shanghai Eastern Scholar Program (J50201) (HZ). VSB thanks NIH grant 1R01GM106121-01A1 and computational time from NERSC.
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URL
http://www.pnas.org/content/early/2018/04/05/1713026115/tab-figures-data
URI
http://hdl.handle.net/10023/16171

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