6n5c
Crystal structure of the catalytic domain of PPIP5K2 in complex with AMPPNP and 5-PCF2Am-InsP5
Structural highlights
FunctionVIP2_HUMAN Bifunctional inositol kinase that acts in concert with the IP6K kinases IP6K1, IP6K2 and IP6K3 to synthesize the diphosphate group-containing inositol pyrophosphates diphosphoinositol pentakisphosphate, PP-InsP5, and bis-diphosphoinositol tetrakisphosphate, (PP)2-InsP4. PP-InsP5 and (PP)2-InsP4, also respectively called InsP7 and InsP8, regulate a variety of cellular processes, including apoptosis, vesicle trafficking, cytoskeletal dynamics, exocytosis, insulin signaling and neutrophil activation. Phosphorylates inositol hexakisphosphate (InsP6) at positions 1 or 3 to produce PP-InsP5 which is in turn phosphorylated by IP6Ks to produce (PP)2-InsP4. Alternatively, phosphorylates at position 1 or 3 PP-InsP5, produced by IP6Ks from InsP6, to produce (PP)2-InsP4.[1] [2] Publication Abstract from PubMedDiphosphoinositol phosphates (PP-InsPs) are an evolutionarily ancient group of signalling molecules that are essential to cellular and organismal homeostasis. As the detailed mechanisms of PP-InsP signalling begin to emerge, synthetic analogues of PP-InsPs containing stabilised mimics of the labile diphosphate group can provide valuable investigational tools. We synthesised 5-PCF2Am-InsP5 (1), a novel fluorinated phosphonate analogue of 5-PP-InsP5, and obtained an X-ray crystal structure of 1 in complex with diphosphoinositol pentakisphosphate kinase 2 (PPIP5K2). 5-PCF2Am-InsP5 binds to the kinase domain of PPIP5K2 in a similar orientation to that of the natural substrate 5-PP-InsP5 and the PCF2Am structure can mimic many aspects of the diphosphate group in 5-PP-InsP5. We propose that 1, the structural and electronic properties of which are in some ways complementary to those of existing phosphonoacetate and methylenebisphosphonate analogues of 5-PP-InsP5, may be a useful addition to the expanding array of chemical tools for the investigation of signalling by PP-InsPs. The PCF2Am group may also deserve attention for wider application as a diphosphate mimic. Synthesis of an alpha-phosphono-alpha,alpha-difluoroacetamide analogue of the diphosphoinositol pentakisphosphate 5-InsP7.,Riley AM, Wang H, Shears SB, Potter BVL Medchemcomm. 2019 Jun 7;10(7):1165-1172. doi: 10.1039/c9md00163h. eCollection, 2019 Jul 1. PMID:31391889[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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