Synthetic inositol phosphate analogues in complex with PPIP5K2 uncover a substrate capture site as a target for drug discovery

Huanchen Wang, Himali Godage, Andrew Riley, Jeremy D. Weaver, Barry Potter, Stephen B Shears

Research output: Contribution to journalArticle

Abstract

Diphosphoinositol polyphosphates (PP-InsPs) are regulatory molecules that function at the interface of cell signaling and organismic homeostasis. We report the first synthesis of naturallyoccurring 5-PP-InsP4 and a new family of inositol polyphosphate analogues, and we studied their interactions with the PPIP5Ks that synthesize PP-InsPs. Through X-ray analysis of several analogues in crystal complexes with the catalytic domain of PPIP5K, together with biochemical assays and mutagenesis, we show that PPIP5Ks possess a surface-mounted, ligand-binding site adjacent to the catalytic pocket. We conclude that this site facilitates substrate capture from the bulk phase, prior to its transfer into the catalytic pocket; that transfer is described at an atomic level. By demonstrating that catalytic activity of PPIP5K is inhibited through binding of 2,5-diO-Bn-InsP4 to the substrate-capture site, we provide “proof-of-principle” of a new, specific
target for drug discovery.
Original languageEnglish
JournalChemistry & Biology
Publication statusPublished - 2014

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