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dc.contributor.authorHeller, GT
dc.contributor.authorAprile, FA
dc.contributor.authorBonomi, M
dc.contributor.authorCamilloni, C
dc.contributor.authorDe Simone, A
dc.contributor.authorVendruscolo, M
dc.date.accessioned2017-09-26T11:09:05Z
dc.date.available2017-09-26T11:09:05Z
dc.date.issued2017-09-01
dc.identifier.issn0022-2836
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/267399
dc.description.abstractApproximately one-third of the human proteome is made up of proteins that are entirely disordered or that contain extended disordered regions. Although these disordered proteins are closely linked with many major diseases, their binding mechanisms with small molecules remain poorly understood, and a major concern is whether their specificity can be sufficient for drug development. Here, by studying the interaction of a small molecule and a disordered peptide from the oncogene protein c-Myc, we describe a "specific-diffuse" binding mechanism that exhibits sequence specificity despite being of entropic nature. By combining NMR spectroscopy, biophysical measurements, statistical inference, and molecular simulations, we provide a quantitative measure of such sequence specificity and compare it to the case of the interaction of urea, which is diffuse but not specific. To investigate whether this type of binding can generally modify intermolecular interactions, we show that it leads to an inhibition of the aggregation of the peptide. These results suggest that the binding mechanism that we report may create novel opportunities to discover drugs that target disordered proteins in their monomeric states in a specific manner.
dc.description.sponsorshipG.T.H. is supported by the Churchill Scholarship and the Gates Cambridge Trust Scholarship.
dc.languageeng
dc.publisherElsevier
dc.rightsAttribution 4.0 International
dc.rightsAttribution 4.0 International
dc.rightsAttribution 4.0 International
dc.rightsAttribution 4.0 International
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectdisordered proteins
dc.subjectdrug binding
dc.subjectentropy
dc.subjectsmall molecules
dc.subjectspecificity
dc.subjectbiophysical phenomena
dc.subjecthumans
dc.subjectMagnetic Resonance Spectroscopy
dc.subjectmolecular docking simulation
dc.subjectprotein binding
dc.subjectproto-oncogene proteins c-myc
dc.subjectstatistics as topic
dc.subjectthiazoles
dc.titleSequence Specificity in the Entropy-Driven Binding of a Small Molecule and a Disordered Peptide
dc.typeArticle
prism.endingPage2779
prism.issueIdentifier18
prism.publicationDate2017
prism.publicationNameJournal of Molecular Biology
prism.startingPage2772
prism.volume429
dc.identifier.doi10.17863/CAM.13377
dcterms.dateAccepted2017-07-20
rioxxterms.versionofrecord10.1016/j.jmb.2017.07.016
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.licenseref.startdate2017-09-01
dc.contributor.orcidHeller, Gabrielle [0000-0002-5672-0467]
dc.contributor.orcidAprile, Francesco [0000-0002-5040-4420]
dc.contributor.orcidBonomi, Massimilano [0000-0002-7321-0004]
dc.contributor.orcidVendruscolo, Michele [0000-0002-3616-1610]
dc.identifier.eissn1089-8638
rioxxterms.typeJournal Article/Review
cam.issuedOnline2017-07-22
cam.orpheus.successThu Jan 30 10:20:12 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