ArticleChemistry & biology2014
Synthetic inositol phosphate analogs reveal that PPIP5K2 has a surface-mounted substrate capture site that is a target for drug discovery.
Article in Chemistry & biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 64 citations in OpenAlex.
- Structural insights into the development of inhibitors for inositol phosphate kinases.FEBS letters · 2026Review
- Three phosphatase families form a community: The phosphohydrolases that act upon inositol pyrophosphates.FEBS letters · 2026Review
- Inositol pyrophosphate kinases in health and disease.FEBS letters · 2026Review
- Shared genetic architecture between Parkinson's disease and self-reported sleep-related traits implicates theSleep advances : a journal of the Sleep Research Society · 2026Article
- A system-wide investigation into the phosphoregulatory network of TNIK and its cellular implications.Frontiers in bioinformatics · 2026Article
- Acidocalcisome-like vacuoles constitute a feedback-controlled phosphate buffering system for the cytosol.eLife · 2025Article
- Expanding the Inositol Pyrophosphate Toolbox: Stereoselective Synthesis and Application of PP-InsPAngewandte Chemie (International ed. in English) · 2025Article
- A small signaling domain controls PPIP5K phosphatase activity in phosphate homeostasis.Nature communications · 2025Article
- Inositol Phosphate Kinase Architecture: Practical Approaches and Lessons Learned.Methods in molecular biology (Clifton, N.J.) · 2025Review
- Structural insights into the catalytic selectivity of glycosyltransferase SgUGT94-289-3 towards mogrosides.Nature communications · 2024Article
- PPIP5K2 Facilitates Proliferation and Metastasis of Non-Small Lung Cancer (NSCLC) through AKT Signaling Pathway.Cancers · 2024Article
- Fluorination Influences the Bioisostery of Myo-Inositol Pyrophosphate Analogs.Chemistry (Weinheim an der Bergstrasse, Germany) · 2023Article
- Modulation of the substrate specificity of the kinase PDK1 by distinct conformations of the full-length protein.Science signaling · 2023Article
- Expedient synthesis and luminescence sensing of the inositol pyrophosphate cellular messenger 5-PP-InsPChemical science · 2023Article
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- A structural exposé of noncanonical molecular reactivity within the protein tyrosine phosphatase WPD loop.Nature communications · 2022Article
- PPIP5K2 promotes colorectal carcinoma pathogenesis through facilitating DNA homologous recombination repair.Oncogene · 2021Article
- ITPK1 is an InsPMolecular plant · 2021Article
- Dissecting the activation of insulin degrading enzyme by inositol pyrophosphates and their bisphosphonate analogs.Chemical science · 2021Article
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Diphosphoinositol pentakisphosphate kinase 2 (PPIP5K2) is one of the mammalian PPIP5K isoforms responsible for synthesis of diphosphoinositol polyphosphates (inositol pyrophosphates; PP-InsPs), regulatory molecules that function at the interface of cell signaling and organismic homeostasis. The development of drugs that inhibit PPIP5K2 could have both experimental and therapeutic applications. Here, we describe a synthetic strategy for producing naturally occurring 5-PP-InsP4, as well as several inositol polyphosphate analogs, and we study their interactions with PPIP5K2 using biochemical and structural approaches. These experiments uncover an additional ligand-binding site on the surface of PPIP5K2, adjacent to the catalytic pocket. This site facilitates substrate capture from the bulk phase, prior to transfer into the catalytic pocket. In addition to demonstrating a "catch-and-pass" reaction mechanism in a small molecule kinase, we demonstrate that binding of our analogs to the substrate capture site inhibits PPIP5K2. This work suggests that the substrate-binding site offers new opportunities for targeted drug design.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.