4A9C

Crystal structure of human SHIP2 in complex with biphenyl 2,3',4,5',6- pentakisphosphate

Summary for 4A9C

• Entry DOI: 10.2210/pdb4a9c/pdb
• Descriptor: PHOSPHATIDYLINOSITOL-3,4,5-TRISPHOSPHATE 5-PHOSPHATASE 2, BIPHENYL 2,3',4,5',6-PENTAKISPHOSPHATE (3 entities in total)
• Functional Keywords: sgc, phosphatidylinositol, signalling, structural genomics consortium stockholm, magnesium binding, hydrolase, inhibitor
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm, cytosol: O15357
• Total number of polymer chains: 2
• Total formula weight: 73121.81

Authors

Tresaugues, L.,Arrowsmith, C.H.,Berglund, H.,Bountra, C.,Edwards, A.M.,Ekblad, T.,Graslund, S.,Karlberg, T.,Mills, S.J.,Moche, M.,Nyman, T.,Persson, C.,Potter, B.V.L.,Schuler, H.,Thorsell, A.G.,Weigelt, J.,Nordlund, P. (deposition date: 2011-11-25, release date: 2012-05-30, Last modification date: 2023-12-20)

Primary citation

Mills, S.J.,Persson, C.,Cozier, G.,Thomas, M.P.,Tresaugues, L.,Erneux, C.,Riley, A.M.,Nordlund, P.,Potter, B.V.L.
A Synthetic Polyphosphoinositide Headgroup Surrogate in Complex with Ship2 Provides a Rationale for Drug Discovery.
Acs Chem.Biol., 7:822-, 2012

PubMed Abstract: Phosphoinositides 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)P(5)). BiPh(2,3',4,5',6)P(5) is not a SHIP2 substrate but inhibits Ins(1,3,4,5)P(4) hydrolysis with an IC(50) of 24.8 ± 3.0 μM, (K(m) for Ins(1,3,4,5)P(4) is 215 ± 28 μM). Molecular dynamics simulations suggest that when BiPh(2,3',4,5',6)P(5) binds to SHIP2, a flexible loop folds over and encloses the ligand. Compounds targeting such a closed conformation might therefore deliver SHIP2-specific drugs.

PubMed: 22330088
DOI: 10.1021/CB200494D

Experimental method

X-RAY DIFFRACTION (2.1 Å)