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dc.contributor.authorRuepp, M-Den
dc.contributor.authorWei, Haoen
dc.contributor.authorLeuenberger, Men
dc.contributor.authorLochner, Men
dc.contributor.authorThompson, Andrewen
dc.date.accessioned2017-04-10T09:27:46Z
dc.date.available2017-04-10T09:27:46Z
dc.date.issued2017-06-01en
dc.identifier.issn0028-3908
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/263553
dc.description.abstractCrystal structures can identify ligand-receptor interactions and assist the development of novel therapeutics, but experimental challenges sometimes necessitate the use of homologous proteins. Tropisetron is an orthosteric ligand at both 5-HT$_{3}$ and α7 nACh receptors and its binding orientation has been determined in the structural homologue AChBP (pdbid: 2WNC). Co-crystallisation with a structurally-related ligand, granisetron, reveals an almost identical orientation (pdbid; 2YME). However, there is a >1000-fold difference in the affinity of tropisetron at 5-HT$_{3}$ versus α7 nACh receptors, and α7 nACh receptors do not bind granisetron. These striking pharmacological differences prompt questions about which receptor the crystal structures most closely represent and whether the ligand orientations are correct. Here we probe the binding orientation of tropisetron and granisetron at 5-HT$_{3}$ receptors by $\textit{in silico}$ modelling and docking, radioligand binding on cysteine-substituted 5-HT$_{3}$ receptor mutants transiently expressed in HEK 293 cells, and synthetic modification of the ligands. For 15 of the 23 cysteine substitutions, the effects on tropisetron and granisetron were different. Structure-activity relationships on synthesised derivatives of both ligands were also consistent with different orientations, revealing that contrary to the crystallographic evidence from AChBP, the two ligands adopt different orientations in the 5-HT3 receptor binding site. Our results show that even quite structurally similar molecules can adopt different orientations in the same binding site, and that caution may be needed when using homologous proteins to predict ligand binding.
dc.description.sponsorshipThis work was funded by the British Heart Foundation [PG/13/39/3029 to AJT], HOLCIM Stiftung zur Förderung der wissenschaftlichen Fortbildung [to M-DR], the NOMIS Foundation [to M-DR], and the Swiss National Science Foundation [SNSF professorship PP00P2_146321/1 to ML].
dc.languageengen
dc.language.isoenen
dc.publisherElsevier
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectcys-loopen
dc.subjection channelen
dc.subjectreceptoren
dc.subjectradioliganden
dc.subject5-HT(3)en
dc.subjectagonisten
dc.subjectantagonisten
dc.subjectcrystalen
dc.subjectbindingen
dc.subjectgranisetronen
dc.subjecttropisetronen
dc.subjectliganden
dc.subjectstructureen
dc.subjectsynthesisen
dc.titleThe binding orientations of structurally-related ligands can differ; A cautionary noteen
dc.typeArticle
prism.endingPage61
prism.publicationDate2017en
prism.publicationNameNeuropharmacologyen
prism.startingPage48
prism.volume119en
dc.identifier.doi10.17863/CAM.8898
dcterms.dateAccepted2017-01-25en
rioxxterms.versionofrecord10.1016/j.neuropharm.2017.01.023en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2017-06-01en
dc.contributor.orcidThompson, Andrew [0000-0002-7046-6792]
dc.identifier.eissn1873-7064
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idBritish Heart Foundation (PG/13/39/30293)
cam.issuedOnline2017-01-27en
cam.orpheus.successThu Jan 30 12:56:32 GMT 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2100-01-01


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International