Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/97967
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dc.contributor.authorPersson, Camillaen
dc.contributor.authorCozier, Gylesen
dc.contributor.authorTrésaugues, Lionelen
dc.contributor.authorErneux, Christopheen
dc.contributor.authorNordlund, Pären
dc.contributor.authorMills, Stephen J.en
dc.contributor.authorThomas, Mark P.en
dc.contributor.authorRiley, Andrew M.en
dc.contributor.authorPotter, Barry V. L.en
dc.date.accessioned2013-07-25T07:25:39Zen
dc.date.accessioned2019-12-06T19:48:53Z-
dc.date.available2013-07-25T07:25:39Zen
dc.date.available2019-12-06T19:48:53Z-
dc.date.copyright2012en
dc.date.issued2012en
dc.identifier.citationMills, S. J., Persson, C., Cozier, G., Thomas, M. P., Trésaugues, L., Erneux, C., et al. (2012). A Synthetic Polyphosphoinositide Headgroup Surrogate in Complex with SHIP2 Provides a Rationale for Drug Discovery. ACS Chemical Biology, 7(5), 822-828.en
dc.identifier.urihttps://hdl.handle.net/10356/97967-
dc.identifier.urihttp://hdl.handle.net/10220/12267en
dc.description.abstractPhosphoinositides regulate many cellular processes, and cellular levels are controlled by kinases and phosphatases. SHIP2 (SH2 (Src homology 2)-domain-containing inositol-phosphatase-2) plays a critical role in phosphoinositide signaling, cleaving the 5-phosphate from phosphatidylinositol 3,4,5-trisphosphate. SHIP2 is thought to be involved in type-2 diabetes and obesity, conditions that could therefore be open to pharmacological modulation of the enzyme. However, rational design of SHIP2 inhibitors has been limited by the absence of a high-resolution structure. Here, we present a 2.1 Å resolution crystal structure of the phosphatase domain of SHIP2 bound to the synthetic ligand biphenyl 2,3′,4,5′,6-pentakisphosphate (BiPh(2,3′,4,5′,6)P5). BiPh(2,3′,4,5′,6)P5 is not a SHIP2 substrate but inhibits Ins(1,3,4,5)P4 hydrolysis with an IC50 of 24.8 ± 3.0 μM, (Km for Ins(1,3,4,5)P4 is 215 ± 28 μM). Molecular dynamics simulations suggest that when BiPh(2,3′,4,5′,6)P5 binds to SHIP2, a flexible loop folds over and encloses the ligand. Compounds targeting such a closed conformation might therefore deliver SHIP2-specific drugs.en
dc.language.isoenen
dc.relation.ispartofseriesACS chemical biologyen
dc.rights© 2012 American chemical society.en
dc.subjectDRNTU::Science::Biological sciencesen
dc.titleA synthetic polyphosphoinositide headgroup surrogate in complex with SHIP2 provides a rationale for drug discoveryen
dc.typeJournal Articleen
dc.contributor.schoolSchool of Biological Sciencesen
dc.identifier.doihttp://dx.doi.org/10.1021/cb200494den
item.grantfulltextnone-
item.fulltextNo Fulltext-
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