Cyclohexyl Ketone Inhibitors of Pin1 Dock in a Trans-Diaxial Cyclohexane Conformation

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dc.contributor.authorXu, Guoyan G.en
dc.contributor.authorSlebodnick, Carlaen
dc.contributor.authorEtzkorn, Felicia A.en
dc.contributor.departmentChemistryen
dc.date.accessioned2017-04-04T18:07:45Zen
dc.date.available2017-04-04T18:07:45Zen
dc.date.issued2012-09-19en
dc.description.abstractCyclohexyl ketone substrate analogue inhibitors (Ac–pSer-Ψ[C = OCH]-Pip–tryptamine) of Pin1, the cell cycle regulatory peptidyl-prolyl isomerase (PPIase), were designed and synthesized as potential electrophilic acceptors for the Pin1 active site Cys113 nucleophile to test a proposed nucleophilic addition-isomerization mechanism. Because they were weak inhibitors, models of all three stereoisomers were docked into the active site of Pin1. Each isomer consistently minimized to a trans-diaxial cyclohexane conformation. From this, we hypothesize that Pin1 stretches substrates into a trans-pyrrolidine conformation to lower the barrier to isomerization. Our reduced amide inhibitor of Pin1 adopted a similar trans-pyrrolidine conformation in the crystal structure. The molecular model of 1, which mimics the l-Ser-l-Pro stereochemistry, in the Pin1 active site showed a distance of 4.4 Å, and an angle of 31° between Cys113-S and the ketone carbon. The computational models suggest that the mechanism of Pin1 PPIase is not likely to proceed through nucleophilic addition.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0044226en
dc.identifier.issn1932-6203en
dc.identifier.issue9en
dc.identifier.orcidSlebodnick, C [0000-0003-4188-7595]en
dc.identifier.urihttp://hdl.handle.net/10919/76749en
dc.identifier.volume7en
dc.language.isoenen
dc.publisherPLOSen
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000309388400022&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectalzheimers gamma-secretaseen
dc.subjectcis/trans isomerase pin1en
dc.subjectsubstrate recognitionen
dc.subjectproline isomerizationen
dc.subjectprolylen
dc.subjectcyclophilinen
dc.subjectmechanismen
dc.subjectcatalysisen
dc.subjectinactivationen
dc.subjectcalcineurinen
dc.titleCyclohexyl Ketone Inhibitors of Pin1 Dock in a Trans-Diaxial Cyclohexane Conformationen
dc.title.serialPLOS ONEen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/Scienceen
pubs.organisational-group/Virginia Tech/Science/Chemistryen
pubs.organisational-group/Virginia Tech/Science/COS T&R Facultyen

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