ArticleStructure (London, England : 1993)2022
The GTP responsiveness of PI5P4Kβ evolved from a compromised trade-off between activity and specificity.
Article in Structure (London, England : 1993), 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- PI4K and PIPK families in breast cancer: subtype-specific oncogenic mechanisms and precision therapeutic strategies.Molecular biology reports · 2026Review
- Article
- Structural basis for high-affinity inhibitor binding to lipid kinases PIP4K2A and PIP4K2B.Acta crystallographica. Section D, Structural biology · 2026Article
- Article
- IMPDH and GTP Metabolism in Cancer: Mechanisms, Regulation, and Translational Scope.Cancer science · 2025Review
- PI5P4K inhibitors: promising opportunities and challenges.The FEBS journal · 2025Review
- Phosphoinositide kinases in cancer: from molecular mechanisms to therapeutic opportunities.Nature reviews. Cancer · 2025Review
- Multimodal action of KRP203 on phosphoinositide kinases in vitro and in cells.Biochemical and biophysical research communications · 2023Article
- Functional molecular evolution of a GTP sensing kinase: PI5P4Kβ.The FEBS journal · 2023Article
- PIP kinases: A versatile family that demands further therapeutic attention.Advances in biological regulation · 2023Article
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Authors and funding
17 authors.
Funding
Abstract
Unlike most kinases, phosphatidylinositol 5-phosphate 4-kinase β (PI5P4Kβ) utilizes GTP as a physiological phosphate donor and regulates cell growth under stress (i.e., GTP-dependent stress resilience). However, the genesis and evolution of its GTP responsiveness remain unknown. Here, we reveal that PI5P4Kβ has acquired GTP preference by generating a short dual-nucleotide-recognizing motif called the guanine efficient association (GEA) motif. Comparison of nucleobase recognition with 660 kinases and 128 G proteins has uncovered that most kinases and PI5P4Kβ use their main-chain atoms for adenine recognition, while the side-chain atoms are required for guanine recognition. Mutational analysis of the GEA motif revealed that the acquisition of GTP reactivity is accompanied by an extended activity toward inosine triphosphate (ITP) and xanthosine triphosphate (XTP). Along with the evolutionary analysis data that point to strong negative selection of the GEA motif, these results suggest that the GTP responsiveness of PI5P4Kβ has evolved from a compromised trade-off between activity and specificity, underpinning the development of the GTP-dependent stress resilience.
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Registered trials
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.