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dc.contributor.authorKukic, Predrag
dc.contributor.authorAlvin Leung, Hoi Tik
dc.contributor.authorBemporad, Francesco
dc.contributor.authorAprile, Francesco A
dc.contributor.authorKumita, Janet R
dc.contributor.authorDe Simone, Alfonso
dc.contributor.authorCamilloni, Carlo
dc.contributor.authorVendruscolo, Michele
dc.date.accessioned2015-05-20T11:03:32Z
dc.date.available2015-05-20T11:03:32Z
dc.date.issued2015-04-07
dc.identifier.citationKukic et al Structure Volume 23, Issue 4, 7 April 2015, Pages 745–753. DOI: 10.1016/j.str.2014.12.020
dc.identifier.issn0969-2126
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/247847
dc.description.abstractLymphocyte function-associated antigen 1 (LFA-1) is an integrin that transmits information in two directions across the plasma membrane of leukocytes, in so-called outside-in and inside-out signaling mechanisms. To investigate the structural basis of these mechanisms, we studied the conformational space of the apo I-domain using replica-averaged metadynamics simulations in combination with nuclear magnetic resonance chemical shifts. We thus obtained a free energy landscape that reveals the existence of three conformational substates of this domain. The three substates include conformations similar to existing crystallographic structures of the low-affinity I-domain, the inactive I-domain with an allosteric antagonist inhibitor bound underneath α helix 7, and an intermediate affinity state of the I-domain. The multiple substates were validated with residual dipolar coupling measurements. These results suggest that the presence of three substates in the apo I-domain enables the precise regulation of the binding process that is essential for the physiological function of LFA-1.
dc.description.sponsorshipThis study was supported by the Wellcome Trust and the BBSRC.
dc.languageEnglish
dc.language.isoen
dc.publisherCell Press
dc.rightsAttribution 2.0 UK: England & Wales
dc.rights.urihttp://creativecommons.org/licenses/by/2.0/uk/
dc.titleStructure and dynamics of the integrin LFA-1 I-domain in the inactive state underlie its inside-out/outside-in signaling and allosteric mechanisms.
dc.typeArticle
dc.description.versionThis is the final version of the article. It first appeared from Cell Press via http://dx.doi.org/10.1016/j.str.2014.12.020
prism.endingPage753
prism.publicationDate2015
prism.publicationNameStructure
prism.startingPage745
prism.volume23
dc.rioxxterms.funderWellcome Trust
dc.rioxxterms.funderBBSRC
dcterms.dateAccepted2014-12-06
rioxxterms.versionofrecord10.1016/j.str.2014.12.020
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2015-03-12
dc.contributor.orcidAprile, Francesco [0000-0002-5040-4420]
dc.contributor.orcidKumita, Janet [0000-0002-3887-4964]
dc.contributor.orcidVendruscolo, Michele [0000-0002-3616-1610]
dc.identifier.eissn1878-4186
rioxxterms.typeJournal Article/Review
cam.issuedOnline2015-03-12


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Attribution 2.0 UK: England & Wales
Except where otherwise noted, this item's licence is described as Attribution 2.0 UK: England & Wales