Coordination complex SH2 domain proteomimetics: an alternative approach to disrupting oncogenic protein-protein interactions.
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ABSTRACT:
SUBMITTER: Drewry JA
PROVIDER: S-EPMC2910512 | biostudies-literature | 2010 Feb
REPOSITORIES: biostudies-literature
Publications
Coordination complex SH2 domain proteomimetics: an alternative approach to disrupting oncogenic protein-protein interactions.
Drewry Joel A JA Fletcher Steven S Yue Peibin P Marushchak Denys D Zhao Wei W Sharmeen Sumaiya S Zhang Xiaolei X Schimmer Aaron D AD Gradinaru Claudiu C Turkson James J Gunning Patrick T PT
Chemical communications (Cambridge, England) 20091201 6
We report the first application of coordination complexes as functional proteomimetics of the Src homology 2 (SH2) phosphopeptide-binding domain. As a proof-of-concept, functionalized bis-dipicolylamine (BDPA) copper(ii) complexes are shown to disrupt oncogenic Stat3-Stat3 protein complexes and elicit promising anti-tumour activity. ...[more]
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Project description:Signaling proteins are localized and regulated by Src homology 2 domains which recognize phosphotyrosine-containing sequences. Recently, noncanonical ligands have been proposed for Src homology 2 domains including that of Abl and its breakpoint cluster region fusion, which causes chronic myelogenous leukemia. Here, the Abl Src homology 2 domain's binding sites and affinities for phosphotyrosine- and phosphoserine-containing motifs, phosphoinositides as well as a pyridone-based peptidomimetic inhibitor were determined using nuclear magnetic resonance spectroscopy in order to define their roles. The cognate Crk peptide ligand was bound with an affinity of 69 microM and, like the higher affinity peptidomimetic, engages the phosphotyrosine and +3 hydrophobic pockets while putative phosphoserine-containing breakpoint cluster region ligands are ruled out. Surprisingly, phosphatidylinositol 4, 5 bisphosphate interacts with an overlapping site through an electrostatic mechanism that does not appear to involve hydrophobic insertion into micelles. The conserved Arg36 residue in the FLVRES motif is required for both phosphotyrosine binding and for localization to phosphatidylinositol 4, 5 bisphosphate-containing liposomes, while Arg59 in the betaD strand is necessary for the phosphoinositide interaction. Thus the Src homology 2 domain of Abl, a myristoylated and membrane-localized protein, is able to interact directly with phosphoinositides through a multifunctional basic site that overlaps the phosphotyrosine pocket.
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2007-01-08 | GSE5619 | GEO