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dc.contributor.authorPennell, Simon
dc.contributor.authorWestcott, Sarah
dc.contributor.authorOrtiz-Lombardía, Miguel
dc.contributor.authorPatel, Dony
dc.contributor.authorLi, Jiejin
dc.contributor.authorNott, Timothy J.
dc.contributor.authorMohammed, Duaa
dc.contributor.authorBuxton, Roger S.
dc.contributor.authorYaffe, Michael B.
dc.contributor.authorVerma, Chandra
dc.contributor.authorSmerdon, Stephen J.
dc.date.accessioned2015-03-20T18:16:37Z
dc.date.available2015-03-20T18:16:37Z
dc.date.issued2010-12
dc.date.submitted2010-09
dc.identifier.issn09692126
dc.identifier.issn1878-4186
dc.identifier.urihttp://hdl.handle.net/1721.1/96137
dc.description.abstractSummary: FHA domains are well established as phospho-dependent binding modules mediating signal transduction in Ser/Thr kinase signaling networks in both eukaryotic and prokaryotic species. Although they are unique in binding exclusively to phosphothreonine, the basis for this discrimination over phosphoserine has remained elusive. Here, we attempt to dissect overall binding specificity at the molecular level. We first determined the optimal peptide sequence for Rv0020c FHA domain binding by oriented peptide library screening. This served as a basis for systematic mutagenic and binding analyses, allowing us to derive relative thermodynamic contributions of conserved protein and peptide residues to binding and specificity. Structures of phosphopeptide-bound and uncomplexed Rv0020c FHA domain then directed molecular dynamics simulations which show how the extraordinary discrimination in favor of phosphothreonine occurs through formation of additional hydrogen-bonding networks that are ultimately stabilized by van der Waals interactions of the phosphothreonine γ-methyl group with a conserved pocket on the FHA domain surface.en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (GM60594)en_US
dc.description.sponsorshipMedical Research Council (Great Britain)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (GM68762)en_US
dc.language.isoen_US
dc.publisherElsevier B.V.en_US
dc.relation.isversionofhttp://dx.doi.org/10.1016/j.str.2010.09.014en_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.sourceElsevieren_US
dc.titleStructural and Functional Analysis of Phosphothreonine-Dependent FHA Domain Interactionsen_US
dc.typeArticleen_US
dc.identifier.citationPennell, Simon, Sarah Westcott, Miguel Ortiz-Lombardía, Dony Patel, Jiejin Li, Timothy J. Nott, Duaa Mohammed, et al. “Structural and Functional Analysis of Phosphothreonine-Dependent FHA Domain Interactions.” Structure 18, no. 12 (December 2010): 1587–1595. © 2010 Elsevier Ltd.en_US
dc.contributor.departmentDavid H. Koch Institute for Integrative Cancer Research at MITen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.mitauthorMohammed, Duaaen_US
dc.contributor.mitauthorYaffe, Michael B.en_US
dc.relation.journalStructureen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsPennell, Simon; Westcott, Sarah; Ortiz-Lombardía, Miguel; Patel, Dony; Li, Jiejin; Nott, Timothy J.; Mohammed, Duaa; Buxton, Roger S.; Yaffe, Michael B.; Verma, Chandra; Smerdon, Stephen J.en_US
dc.identifier.orcidhttps://orcid.org/0000-0002-9547-3251
mit.licensePUBLISHER_POLICYen_US


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