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dc.contributor.authorChan, Danielen
dc.contributor.authorMendes, Ven
dc.contributor.authorThomas, Sherineen
dc.contributor.authorMcConnell, Brendanen
dc.contributor.authorMatak Vinkovic, Dijanaen
dc.contributor.authorCoyne, Anthonyen
dc.contributor.authorBlundell, Tomen
dc.contributor.authorAbell, Chrisen
dc.date.accessioned2017-08-18T10:12:50Z
dc.date.available2017-08-18T10:12:50Z
dc.date.issued2017-06-09en
dc.identifier.issn1433-7851
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/266609
dc.description.abstractNative nanoelectrospray ionization mass spectrometry is an underutilized technique for fragment screening. In this study, the first demonstration is provided of the use of native mass spectrometry for screening fragments against a protein–DNA interaction. EthR is a transcriptional repressor of EthA expression in Mycobacterium tuberculosis (Mtb) that reduces the efficacy of ethionamide, a second‐line antitubercular drug used to combat multidrug‐resistant Mtb strains. A small‐scale fragment screening campaign was conducted against the EthR–DNA interaction using native mass spectrometry, and the results were compared with those from differential scanning fluorimetry, a commonly used primary screening technique. Hits were validated by surface plasmon resonance and X‐ray crystallography. The screening campaign identified two new fragments that disrupt the EthR–DNA interaction in vitro (IC50=460–610 μm) and bind to the hydrophobic channel of the EthR dimer.
dc.language.isoenen
dc.publisherJohn Wiley & Sons Ltd.
dc.subjectmass spectrometryen
dc.subjectEthRen
dc.subjectfragment screeningen
dc.subjectnative mass spectrometryen
dc.subjectprotein–DNA interactionsen
dc.subjecttuberculosisen
dc.titleFragment screening against the EthR-DNA interaction by native mass spectrometryen
dc.typeArticle
prism.endingPage7491
prism.issueIdentifier26en
prism.publicationDate2017en
prism.publicationNameAngewandte Chemie - International Editionen
prism.startingPage7488
prism.volume56en
dc.identifier.doi10.17863/CAM.9964
dcterms.dateAccepted2017-03-20en
rioxxterms.versionofrecord10.1002/anie.201702888en
rioxxterms.versionAMen
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2017-06-09en
dc.contributor.orcidThomas, Sherine [0000-0003-1152-4312]
dc.contributor.orcidMcConnell, Brendan [0000-0001-9002-9808]
dc.contributor.orcidMatak Vinkovic, Dijana [0000-0003-4093-1443]
dc.contributor.orcidCoyne, Anthony [0000-0003-0205-5630]
dc.contributor.orcidBlundell, Tom [0000-0002-2708-8992]
dc.contributor.orcidAbell, Chris [0000-0001-9174-1987]
dc.identifier.eissn1521-3773
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MR/M026302/1)
pubs.funder-project-idMedical Research Council (MR/N501864/1)
cam.issuedOnline2017-05-17en
dc.identifier.urlhttps://onlinelibrary.wiley.com/doi/full/10.1002/anie.201702888en
cam.orpheus.successThu Jan 30 13:00:13 GMT 2020 - Embargo updated*
rioxxterms.freetoread.startdate2018-05-17


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