Allosteric site on SHIP2 identified through fluorescent ligand screening and crystallography: a potential new target for intervention

Whitfield, Hayley, Hemmings, Andrew M., Mills, Stephen J., Baker, Kendall, White, Gaye, Rushworth, Stuart, Riley, Andrew M., Potter, Barry V. L. and Brearley, Charles A. (2021) Allosteric site on SHIP2 identified through fluorescent ligand screening and crystallography: a potential new target for intervention. Journal of Medicinal Chemistry, 64 (7). 3813–3826. ISSN 0022-2623

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Abstract

Src Homology 2 domain-containing inositol phosphate phosphatase 2 (SHIP2) is one of ten human inositol phosphate 5-phosphatases. One of its physiological functions is dephosphorylation of phosphatidylinositol 3,4,5-trisphosphate, PtdIns(3,4,5)P3. It is therefore a therapeutic target for pathophysiologies dependent on PtdIns(3,4,5)P3 and PtdIns(3,4)P2. Therapeutic interventions are limited by the dearth of crystallographic data describing ligand/inhibitor binding. An active site-directed fluorescent probe facilitated screening of compound libraries for SHIP2 ligands. With two additional orthogonal assays, several ligands including galloflavin were identified as low micromolar Ki inhibitors. One ligand, an oxo-linked ethylene-bridged dimer of benzene 1,2,4-trisphosphate, was shown to be an uncompetitive inhibitor that binds to a regulatory site on the catalytic domain. We posit that binding of ligands to this site restrains L4 loop motions that are key to interdomain communications that accompany high catalytic activity with phosphoinositide substrate. This site may, therefore, be a future druggable target for medicinal chemistry.

Item Type: Article
Faculty \ School: Faculty of Science > School of Biological Sciences
Faculty of Science > School of Chemistry
Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 26 Feb 2021 01:01
Last Modified: 21 Jul 2021 01:44
URI: https://ueaeprints.uea.ac.uk/id/eprint/79334
DOI: 10.1021/acs.jmedchem.0c01944

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