ArticleProtein science : a publication of the Protein Society2014
Engineering of an isolated p110α subunit of PI3Kα permits crystallization and provides a platform for structure-based drug design.
Article in Protein science : a publication of the Protein Society, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 27 citations in OpenAlex.
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- Improved production of class I phosphatidylinositol 4,5-bisphosphate 3-kinase.Protein expression and purification · 2025Article
- Rapid, potent, and persistent covalent chemical probes to deconvolute PI3Kα signaling.Chemical science · 2024Article
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- Article
- Characterisation of a cyclic peptide that binds to the RAS binding domain of phosphoinositide 3-kinase p110α.Scientific reports · 2023Article
- Synthesis, Molecular Docking, In Vitro and In Vivo Studies of Novel Dimorpholinoquinazoline-Based Potential Inhibitors of PI3K/Akt/mTOR Pathway.International journal of molecular sciences · 2022Article
- Covalent Proximity Scanning of a Distal Cysteine to Target PI3Kα.Journal of the American Chemical Society · 2022Article
- Class I PI3K Biology.Current topics in microbiology and immunology · 2022Article
- Integrative Bioinformatics Study of Tangeretin Potential Targets for Preventing Metastatic Breast Cancer.Evidence-based complementary and alternative medicine : eCAM · 2021Article
- Structural Determinants of Isoform Selectivity in PI3K Inhibitors.Biomolecules · 2019Review
- Discovering new PI3Kα inhibitors with a strategy of combining ligand-based and structure-based virtual screening.Journal of computer-aided molecular design · 2018Article
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7 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
PI3Kα remains an attractive target for the development of anticancer targeted therapy. A number of p110α crystal structures in complex with the nSH2-iSH2 fragment of p85 regulatory subunit have been reported, including a few small molecule co-crystal structures, but the utilization of this crystal form is limited by low diffraction resolution and a crystal packing artifact that partially blocks the ATP binding site. Taking advantage of recent data on the functional characterization of the lipid binding properties of p110α, we designed a set of novel constructs allowing production of isolated stable p110α subunit missing the Adapter Binding Domain and lacking or featuring a modified C-terminal lipid binding motif. While this protein is not catalytically competent to phosphorylate its substrate PIP2, it retains ligand binding properties as indicated by direct binding studies with a pan-PI3Kα inhibitor. Additionally, we determined apo and PF-04691502 bound crystal structures of the p110α (105-1048) subunit at 2.65 and 2.85 Å, respectively. Comparison of isolated p110α(105-1048) with the p110α/p85 complex reveals a high degree of structural similarity, which validates suitability of this catalytically inactive p110α for iterative SBDD. Importantly, this crystal form of p110α readily accommodates the binding of noncovalent inhibitor by means of a fully accessible ATP site. The strategy presented here can be also applied to structural studies of other members of PI3KIA family.
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