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dc.contributor.authorJaneček, Matej
dc.contributor.authorRossmann, Maxim
dc.contributor.authorSharma, Pooja
dc.contributor.authorEmery, Amy
dc.contributor.authorHuggins, David J
dc.contributor.authorStockwell, Simon R
dc.contributor.authorStokes, Jamie E
dc.contributor.authorTan, Yaw S
dc.contributor.authorAlmeida, Estrella Guarino
dc.contributor.authorHardwick, Bryn
dc.contributor.authorNarvaez, Ana J
dc.contributor.authorHyvönen, Marko
dc.contributor.authorSpring, David R
dc.contributor.authorMcKenzie, Grahame J
dc.contributor.authorVenkitaraman, Ashok R
dc.date.accessioned2016-07-01T13:24:37Z
dc.date.available2016-07-01T13:24:37Z
dc.date.issued2016-06-24
dc.identifier.issn2045-2322
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/256569
dc.description.abstractThe essential mitotic kinase Aurora A (AURKA) is controlled during cell cycle progression via two distinct mechanisms. Following activation loop autophosphorylation early in mitosis when it localizes to centrosomes, AURKA is allosterically activated on the mitotic spindle via binding to the microtubule-associated protein, TPX2. Here, we report the discovery of AurkinA, a novel chemical inhibitor of the AURKA-TPX2 interaction, which acts via an unexpected structural mechanism to inhibit AURKA activity and mitotic localization. In crystal structures, AurkinA binds to a hydrophobic pocket (the 'Y pocket') that normally accommodates a conserved Tyr-Ser-Tyr motif from TPX2, blocking the AURKA-TPX2 interaction. AurkinA binding to the Y- pocket induces structural changes in AURKA that inhibit catalytic activity in vitro and in cells, without affecting ATP binding to the active site, defining a novel mechanism of allosteric inhibition. Consistent with this mechanism, cells exposed to AurkinA mislocalise AURKA from mitotic spindle microtubules. Thus, our findings provide fresh insight into the catalytic mechanism of AURKA, and identify a key structural feature as the target for a new class of dual-mode AURKA inhibitors, with implications for the chemical biology and selective therapeutic targeting of structurally related kinases.
dc.description.sponsorshipWe are grateful for the access and support at beamlines i02, i03 and i04-1 at Diamond Light Source at Harwell, UK (proposal MX9007 and MX9537) and at beamline Proxima1 at the SOLEIL Synchrotron, Gif-sur-Yvette, France. We are grateful for access and support from the X-ray and biophysics facilities (Dept. of Biochemistry) and the screening/imaging facility (MRC Cancer Unit). M.J. was supported by a Cancer Research UK studentship held in the labs of DS and ARV, PS and MR by a Wellcome Trust Strategic Award to ARV and MH, and DJH, BH, AJN and GM by grants from the UK Medical Research Council to ARV.
dc.languageEnglish
dc.language.isoen
dc.publisherSpringer Science and Business Media LLC
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.titleAllosteric modulation of AURKA kinase activity by a small-molecule inhibitor of its protein-protein interaction with TPX2.
dc.typeArticle
dc.description.versionThis is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/srep28528
prism.number28528
prism.publicationDate2016
prism.publicationNameSci Rep
prism.volume6
dc.identifier.doi10.17863/CAM.509
dcterms.dateAccepted2016-06-03
rioxxterms.versionofrecord10.1038/srep28528
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.licenseref.startdate2016-06-24
dc.contributor.orcidRossmann, Maxim [0000-0001-8811-3277]
dc.contributor.orcidHuggins, David [0000-0003-1579-2496]
dc.contributor.orcidStockwell, Simon [0000-0002-3345-8945]
dc.contributor.orcidSpring, David [0000-0001-7355-2824]
dc.identifier.eissn2045-2322
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (G1001522)
pubs.funder-project-idWellcome Trust (090340/Z/09/Z)
pubs.funder-project-idMedical Research Council (MC_UU_12022/1)
pubs.funder-project-idRoyal Society (WM150022)
pubs.funder-project-idEuropean Research Council (279337)
pubs.funder-project-idEngineering and Physical Sciences Research Council (EP/J016012/1)
pubs.funder-project-idMedical Research Council (MR/L007266/1)
pubs.funder-project-idEngineering and Physical Sciences Research Council (EP/K039520/1)
pubs.funder-project-idMRC (MC_UU_12022/8)
cam.issuedOnline2016-06-24


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International