7Z75
PI3KC2a core in complex with PITCOIN3
Summary for 7Z75
| Entry DOI | 10.2210/pdb7z75/pdb |
| Descriptor | Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha, ~{N}-[4-[3-(methylsulfonylamino)phenyl]-1,3-thiazol-2-yl]-2-[4-oxidanylidene-3-(2-phenylethyl)pteridin-2-yl]sulfanyl-ethanamide, 1,2-ETHANEDIOL, ... (5 entities in total) |
| Functional Keywords | pi3kc2 alpha, kinase, transferase |
| Biological source | Mus musculus (house mouse) More |
| Total number of polymer chains | 1 |
| Total formula weight | 103237.85 |
| Authors | Lo, W.T.,Roske, Y.,Daumke, O.,Haucke, V. (deposition date: 2022-03-15, release date: 2022-08-31, Last modification date: 2024-02-07) |
| Primary citation | Lo, W.T.,Belabed, H.,Kucukdisli, M.,Metag, J.,Roske, Y.,Prokofeva, P.,Ohashi, Y.,Horatscheck, A.,Cirillo, D.,Krauss, M.,Schmied, C.,Neuenschwander, M.,von Kries, J.P.,Medard, G.,Kuster, B.,Perisic, O.,Williams, R.L.,Daumke, O.,Payrastre, B.,Severin, S.,Nazare, M.,Haucke, V. Development of selective inhibitors of phosphatidylinositol 3-kinase C2 alpha. Nat.Chem.Biol., 19:18-27, 2023 Cited by PubMed Abstract: Phosphatidylinositol 3-kinase type 2α (PI3KC2α) and related class II PI3K isoforms are of increasing biomedical interest because of their crucial roles in endocytic membrane dynamics, cell division and signaling, angiogenesis, and platelet morphology and function. Herein we report the development and characterization of PhosphatidylInositol Three-kinase Class twO INhibitors (PITCOINs), potent and highly selective small-molecule inhibitors of PI3KC2α catalytic activity. PITCOIN compounds exhibit strong selectivity toward PI3KC2α due to their unique mode of interaction with the ATP-binding site of the enzyme. We demonstrate that acute inhibition of PI3KC2α-mediated synthesis of phosphatidylinositol 3-phosphates by PITCOINs impairs endocytic membrane dynamics and membrane remodeling during platelet-dependent thrombus formation. PITCOINs are potent and selective cell-permeable inhibitors of PI3KC2α function with potential biomedical applications ranging from thrombosis to diabetes and cancer. PubMed: 36109648DOI: 10.1038/s41589-022-01118-z PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.59 Å) |
Structure validation
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