Novel Inositol Phospholipid Headgroup Surrogate Crystallized in the Pleckstrin Homology Domain of Protein Kinase Bα

ACS Chemical Biology (Impact Factor: 5.33). 05/2007; 2(4):242-6. DOI: 10.1021/cb700019r
Source: PubMed


Protein kinase B (PKB/Akt) plays a key role in cell signaling. The PH domain of PKB binds phosphatidylinositol 3,4,5-trisphosphate translocating PKB to the plasma membrane for activation by 3-phosphoinositide-dependent protein kinase 1. The crystal structure of the headgroup inositol 1,3,4,5-tetrakisphosphate Ins(1,3,4,5)P4-PKB complex facilitates in silico ligand design. The novel achiral analogue benzene 1,2,3,4-tetrakisphosphate (Bz(1,2,3,4)P4) possesses phosphate regiochemistry different from that of Ins(1,3,4,5)P4 and surprisingly binds with similar affinity as the natural headgroup. Bz(1,2,3,4)P4 co-crystallizes with the PKBalpha PH domain in a fashion also predictable in silico. The 2-phosphate of Bz(1,2,3,4)P4 does not interact with any residue, and the D5-phosphate of Ins(1,3,4,5)P4 is not mimicked by Bz(1,2,3,4)P4. Bz(1,2,3,4)P4 is an example of a simple inositol phosphate surrogate crystallized in a protein, and this approach could be applied to design modulators of inositol polyphosphate binding proteins.

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Available from: Stephen T Safrany
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    • "Indeed we reported that inositol 1,3,4,5,6- pentakisphosphate (InsP 5 ) specifically blocks Akt activation and possesses pro-apoptotic (Razzini et al, 2000; Piccolo et al, 2004), anti-angiogenic and anti-tumour activity in vivo (Maffucci et al, 2005). In addition, some of us recently demonstrated the targeting of the Akt PH domain with an unusual inositol polyphosphate mimic (Mills et al, 2007). Other phosphatidylinositol-based Akt inhibitors also act by inhibiting Akt targeting to the plasma membrane, including ether lipid analogues and PH domain-targeting inhibitors (Kozikowski et al, 2003; Gills et al, 2006; Crowell et al, 2007) such as perifosine, the most developed Akt inhibitor currently available (Kondapaka et al, 2003). "
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    ABSTRACT: Nearly 25 years ago the first function of an inositol phosphate, namely Ins(1,4,5)P3, was reported to act as a "second messenger" to mobilize calcium from the endoplasmic reticulum (ER). Since this discovery, many other inositol phosphates and the kinases and phosphatases that generate these inositol phosphates have subsequently been discovered. However, the function of these "higher order" inositol phosphates in biological processes, if any, has remained a mystery. Interest in higher order inositol phosphates, such as Ins(1,3,4,5)P4, was renewed this year following reports of novel roles for these molecules in distinct processes within the immune system ranging from T cell development, B cell development and tolerance induction, as well as neutrophil and mast cell function. In this review, we will touch upon recent advances in inositol phosphate function in mammalian cells. More specifically, we will highlight new studies that have identified novel functions for specific higher order inositol phosphates, such as Ins(1,3,4,5)P4, in the immune system.
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