3TC5
Selective targeting of disease-relevant protein binding domains by O-phosphorylated natural product derivatives
Summary for 3TC5
| Entry DOI | 10.2210/pdb3tc5/pdb |
| Related | 1PIN 2ITK 2Q5A 2ZR6 |
| Descriptor | Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, (11alpha,16alpha)-9-fluoro-11,17-dihydroxy-16-methyl-3,20-dioxopregna-1,4-dien-21-yl dihydrogen phosphate, HEXAETHYLENE GLYCOL, ... (4 entities in total) |
| Functional Keywords | pin1 mutant (r14a), oncogenic transformation, small molecule, cell cycle, rotamase, phosphoprotein, nucleus, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Nucleus : Q13526 |
| Total number of polymer chains | 1 |
| Total formula weight | 19222.24 |
| Authors | Graeber, M.,Janczyk, W.,Sperl, B.,Elumalai, N.,Kozany, C.,Hausch, F.,Holak, T.A.,Berg, T. (deposition date: 2011-08-08, release date: 2011-08-31, Last modification date: 2023-09-13) |
| Primary citation | Graber, M.,Janczyk, W.,Sperl, B.,Elumalai, N.,Kozany, C.,Hausch, F.,Holak, T.A.,Berg, T. Selective targeting of disease-relevant protein binding domains by o-phosphorylated natural product derivatives. Acs Chem.Biol., 6:1008-1014, 2011 Cited by PubMed Abstract: Phosphorylation-dependent protein binding domains are crucially important for intracellular signaling pathways and thus highly relevant targets in chemical biology. By screening of chemical libraries against 12 structurally diverse phosphorylation-dependent protein binding domains, we have identified fosfosal and dexamethasone-21-phosphate as selective inhibitors of two antitumor targets: the SH2 domain of the transcription factor STAT5b and the substrate-binding domain of the peptidyl-prolyl isomerase Pin1, respectively. Both compounds are phosphate prodrugs with documented clinical use as anti-inflammatory agents in humans and were discovered with a high hit rate from a small subgroup within the screening library. Our study indicates O-phosphorylation of appropriately preselected natural products or natural product derivatives as a generally applicable strategy for the identification of non-reactive and non-peptidic ligands of phosphorylation-dependent protein binding domains. Moreover, our data indicate that it would be advisable to monitor the bioactivities of clinically used prodrugs in their uncleaved state against phosphorylation-dependent protein binding domains. PubMed: 21797253DOI: 10.1021/cb2001796 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.4 Å) |
Structure validation
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