6SQU

Crystal structure of human SHIP2 catalytic domain in complex with 1,2,4 Dimer

Summary for 6SQU

• Entry DOI: 10.2210/pdb6squ/pdb
• Descriptor: Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2, 5,5'-(ethane-1,2-diylbis(oxy))bis(benzene-5,4,2,1,-tetrayl)hexakisphosphate (3 entities in total)
• Functional Keywords: hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 73277.84

Authors

Whitfield, H.,Brearley, C.A.,Hemmings, A.M. (deposition date: 2019-09-04, release date: 2021-01-13, Last modification date: 2024-01-24)

Primary citation

Whitfield, H.,Hemmings, A.M.,Mills, S.J.,Baker, K.,White, G.,Rushworth, S.,Riley, A.M.,Potter, B.V.L.,Brearley, C.A.
Allosteric Site on SHIP2 Identified Through Fluorescent Ligand Screening and Crystallography: A Potential New Target for Intervention.
J.Med.Chem., 64:3813-3826, 2021

PubMed Abstract: Src homology 2 domain-containing inositol phosphate phosphatase 2 (SHIP2) is one of the 10 human inositol phosphate 5-phosphatases. One of its physiological functions is dephosphorylation of phosphatidylinositol 3,4,5-trisphosphate, PtdIns(3,4,5)P. It is therefore a therapeutic target for pathophysiologies dependent on PtdIns(3,4,5)P and PtdIns(3,4)P. 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.

PubMed: 33724834
DOI: 10.1021/acs.jmedchem.0c01944

Experimental method

X-RAY DIFFRACTION (2.27 Å)