2 research outputs found
Retraction of Mechanistic Basis for Epstein–Barr Virus Ribonucleotide-reductase Small-Subunit Function
Retraction of Mechanistic Basis for Epstein–Barr Virus Ribonucleotide-reductase Small-Subunit Functio
A Synthetic Polyphosphoinositide Headgroup Surrogate in Complex with SHIP2 Provides a Rationale for Drug Discovery
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<sub>5</sub>). BiPh(2,3′,4,5′,6)P<sub>5</sub> is not a SHIP2
substrate but inhibits Ins(1,3,4,5)P<sub>4</sub> hydrolysis with an
IC<sub>50</sub> of 24.8 ± 3.0 μM, (<i>K</i><sub>m</sub> for Ins(1,3,4,5)P<sub>4</sub> is 215 ± 28 μM).
Molecular dynamics simulations suggest that when BiPh(2,3′,4,5′,6)P<sub>5</sub> binds to SHIP2, a flexible loop folds over and encloses the
ligand. Compounds targeting such a closed conformation might therefore
deliver SHIP2-specific drugs