title: A synthetic polyphosphoinositide headgroup surrogate in complex with SHIP2 provides a rationale for drug discovery.
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.
authors.affiliation: Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, U.K.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Mills
authors.forename: Camilla
authors.initials: C
authors.lastname: Persson
authors.forename: Gyles
authors.initials: G
authors.lastname: Cozier
authors.forename: Mark P
authors.initials: MP
authors.lastname: Thomas
authors.forename: Lionel
authors.initials: L
authors.lastname: Trésaugues
authors.forename: Christophe
authors.initials: C
authors.lastname: Erneux
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Riley
authors.forename: Pär
authors.initials: P
authors.lastname: Nordlund
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
mesh_terms: D001713:Biphenyl Compounds / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D010710:Phosphates / Q000737:chemistry* / Q000494:pharmacology*; D018129:Phosphatidylinositol Phosphates / Q000737:chemistry* / Q000494:pharmacology; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D018909:src Homology Domains
chemical_list: D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D010710:Phosphates; D018129:Phosphatidylinositol Phosphates; C519883:biphenyl 2,3',4,5',6-pentakisphosphate; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases