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dc.contributor.authorAhmed, Lucky
dc.contributor.authorZhang, Yuetian
dc.contributor.authorBlock, Eric
dc.contributor.authorBuehl, Michael
dc.contributor.authorCorr, Michael J.
dc.contributor.authorCormanich, Rodrigo A.
dc.contributor.authorGundala, Sivaji
dc.contributor.authorMatsunami, Hiroaki
dc.contributor.authorO'Hagan, David
dc.contributor.authorOzbil, Mehmet
dc.contributor.authorPan, Yi
dc.contributor.authorSekharan, Sivakumar
dc.contributor.authorTen, Nicholas
dc.contributor.authorWang, Mingan
dc.contributor.authorYang, Mingyan
dc.contributor.authorZhang, Qingzhi
dc.contributor.authorZhang, Ruina
dc.contributor.authorBatista, Victor
dc.contributor.authorZhuang, Hanyi
dc.identifier.citationAhmed , 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 .
dc.identifier.otherORCID: /0000-0002-1095-7143/work/62668353
dc.identifier.otherORCID: /0000-0002-0510-5552/work/68281201
dc.descriptionWe 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.en
dc.description.abstractUnderstanding 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.
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen
dc.subjectOdorant receptoren
dc.subjectQuantum mechanicsen
dc.subjectMolecular dynamicsen
dc.subjectQD Chemistryen
dc.subjectQC Physicsen
dc.subjectSDG 3 - Good Health and Well-beingen
dc.titleMolecular mechanism of activation of human musk receptors OR5AN1 and OR1A1 by (R)-muscone and diverse other musk-smelling compoundsen
dc.typeJournal articleen
dc.contributor.institutionUniversity of St Andrews. EaSTCHEMen
dc.contributor.institutionUniversity of St Andrews. School of Chemistryen
dc.contributor.institutionUniversity of St Andrews. Biomedical Sciences Research Complexen
dc.description.statusPeer revieweden

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