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Whitfield, Hayley, Hemmings, Andrew M. 
ORCID: https://orcid.org/0000-0003-3053-3134, Mills, Stephen J., Baker, Kendall, White, Gaye, Rushworth, Stuart, Riley, Andrew M., Potter, Barry V. L. and Brearley, Charles A. ORCID: https://orcid.org/0000-0001-6179-9109
(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 |
| UEA Research Groups: | Faculty of Science > Research Groups > Plant Sciences Faculty of Science > Research Groups > Molecular Microbiology Faculty of Science > Research Centres > Centre for Molecular and Structural Biochemistry Faculty of Science > Research Groups > Chemistry of Life Processes Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 26 Feb 2021 01:01 |
| Last Modified: | 25 Oct 2023 01:40 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/79334 |
| DOI: | 10.1021/acs.jmedchem.0c01944 |
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