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Studying haloanisoles interaction with olfactory receptors

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dc.contributor.authorTeixeira, Carla S. Silva
dc.contributor.authorFerreira, António César Silva
dc.contributor.authorCerqueira, Nuno M. F. S. A.
dc.date.accessioned2017-10-11T15:17:35Z
dc.date.available2017-10-11T15:17:35Z
dc.date.issued2016
dc.description.abstractIn this paper, computational means were used to explain and predict the interaction of several odorant molecules, including three haloanisoles, 2,4,6-trichloroanisole (TCA), 2,4,6-tribromoanisole (TBA), and 2,4,6-trichlorophenol (TCP), with three olfactory receptors (ORs): OR1A1, OR1A2, and OR3A1. As the X-ray structure of these ORs is not known, the three-dimensional structure of each OR was modeled by homology modeling. The structures of these ORs were stabilized by molecular dynamic simulations and the complexes of the odorant molecules with each ORs were generated by molecular docking. The theoretical results have shown that each OR has distinct but well-defined binding regions for each type of odorant molecules (aldehydes and alcohols). In OR3A1, the aldehydes bind in the bottom region of the binding pocket nearby Ser257 and Thr249. In the paralogues OR1A1 and OR1A2, the aldehydes tend to interact in the top region of the binding pocket and close to a positively charged lysine. On the other hand, the alcohols interact in the bottom region of the active site and close to a negatively charged aspartate. These results indicate that when aldehydes and alcohols odorants compete in these two ORs, the aldehydes can block the access of the alcohols odorants to their specific binding site. This observation goes in line with the experimental data that reveals that when the odorant is an aldehyde, a lower quantity of ligand is needed to cause 50% of the maximum response (lower EC50), when compared with the alcohols. The theoretical results have also allowed to explain the differences in the activity of (S)-(−)-citronellol in the wild-type and mutated OR1A1. The theoretical results show that Asn109 has a preponderant role in this matter, since when it is mutated, it leads to a conformational rearrangement of the binding pocket that prevents the interaction of (S)-(−)-citronellol with Asp111 that was shown to be important for the OR activation. The good agreement between the theoretical and experimental results also lead us to study the potential interaction of the haloanisoles, TCA, TBA, and TCP with these ORs. The results have shown that these compounds can compete with other known agonists/antagonists for the access to the binding regions of ORs. These results may partially explain the capability of these compounds to give a musty odor to food and beverages at very low concentrations.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationTEIXEIRA, Carla S. Silva; FERREIRA, António Cesar Silva; CERQUEIRA, Nuno M. F. S. A. - Studying Haloanisoles Interaction with Olfactory Receptors. ACS Chemical Neuroscience. ISSN 1948-7193. Vol. 7, n.º 7 (2016), p. 870–885pt_PT
dc.identifier.doi10.1021/acschemneuro.5b00335pt_PT
dc.identifier.eid84979642559
dc.identifier.issn1948-7193
dc.identifier.pmid27092849
dc.identifier.urihttp://hdl.handle.net/10400.14/22973
dc.identifier.wos000380297500005
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherAmerican Chemical Society
dc.relationIF/01310/2013pt_PT
dc.subjectHaloanisolespt_PT
dc.subjectHomologypt_PT
dc.subjectOlfactory receptorspt_PT
dc.subjectMolecular dynamicspt_PT
dc.subjectMolecular dockingpt_PT
dc.titleStudying haloanisoles interaction with olfactory receptorspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FAGR-ALI%2F121062%2F2010/PT
oaire.citation.endPage885
oaire.citation.issue7
oaire.citation.startPage870
oaire.citation.titleACS Chemical Neurosciencept_PT
oaire.citation.volume7
oaire.fundingStream3599-PPCDT
person.familyNameSilva Teixeira
person.familyNameSilva Ferreira
person.familyNameCerqueira
person.givenNameCarla Sílvia
person.givenNameAntonio Cesar
person.givenNameNuno M. F. Sousa A.
person.identifier.ciencia-id3211-BAEF-3FB0
person.identifier.ciencia-id931A-48DA-23A8
person.identifier.ciencia-idE211-CF2C-4E5D
person.identifier.orcid0000-0002-8422-9392
person.identifier.orcid0000-0002-1188-1021
person.identifier.orcid0000-0003-0342-7424
person.identifier.ridK-7773-2014
person.identifier.ridA-5182-2008
person.identifier.scopus-author-id57160292700
person.identifier.scopus-author-id6507086700
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication2758e735-d927-4cb5-97e3-e0980ad49386
relation.isAuthorOfPublication826c11dd-d070-4b67-ac58-c96675e3f3b8
relation.isAuthorOfPublication5c77eb1d-3c0c-437e-8da0-b13ce8ae4866
relation.isAuthorOfPublication.latestForDiscovery826c11dd-d070-4b67-ac58-c96675e3f3b8
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