Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/97967
Title: A synthetic polyphosphoinositide headgroup surrogate in complex with SHIP2 provides a rationale for drug discovery
Authors: Persson, Camilla
Cozier, Gyles
Trésaugues, Lionel
Erneux, Christophe
Nordlund, Pär
Mills, Stephen J.
Thomas, Mark P.
Riley, Andrew M.
Potter, Barry V. L.
Keywords: DRNTU::Science::Biological sciences
Issue Date: 2012
Source: Mills, S. J., Persson, C., Cozier, G., Thomas, M. P., Trésaugues, L., Erneux, C., et al. (2012). A Synthetic Polyphosphoinositide Headgroup Surrogate in Complex with SHIP2 Provides a Rationale for Drug Discovery. ACS Chemical Biology, 7(5), 822-828.
Series/Report no.: ACS chemical biology
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)P5). BiPh(2,3′,4,5′,6)P5 is not a SHIP2 substrate but inhibits Ins(1,3,4,5)P4 hydrolysis with an IC50 of 24.8 ± 3.0 μM, (Km for Ins(1,3,4,5)P4 is 215 ± 28 μM). Molecular dynamics simulations suggest that when BiPh(2,3′,4,5′,6)P5 binds to SHIP2, a flexible loop folds over and encloses the ligand. Compounds targeting such a closed conformation might therefore deliver SHIP2-specific drugs.
URI: https://hdl.handle.net/10356/97967
http://hdl.handle.net/10220/12267
DOI: 10.1021/cb200494d
Rights: © 2012 American chemical society.
Fulltext Permission: none
Fulltext Availability: No Fulltext
Appears in Collections:SBS Journal Articles

SCOPUSTM   
Citations 10

32
Updated on Feb 5, 2023

Web of ScienceTM
Citations 10

32
Updated on Feb 4, 2023

Page view(s) 50

459
Updated on Feb 5, 2023

Google ScholarTM

Check

Altmetric


Plumx

Items in DR-NTU are protected by copyright, with all rights reserved, unless otherwise indicated.