3C06
Lactobacillus CASEI Thymidylate Synthase Ternary Complex With DUMP and the Phtalimidic Derivative 14C in Multiple Binding Modes-Mode 1
Summary for 3C06
| Entry DOI | 10.2210/pdb3c06/pdb |
| Related | 1TLS 3BNZ 3BYX 3BZ0 3C0A |
| Descriptor | Thymidylate synthase, 2'-DEOXYURIDINE 5'-MONOPHOSPHATE, 2-(2-chloropyridin-4-yl)-4-methyl-1H-isoindole-1,3(2H)-dione, ... (4 entities in total) |
| Functional Keywords | methyltransferase, structure-based drug design, nucleotide biosynthesis, transferase |
| Biological source | Lactobacillus casei |
| Cellular location | Cytoplasm: P00469 |
| Total number of polymer chains | 1 |
| Total formula weight | 37211.32 |
| Authors | Leone, R.,Mangani, S.,Cancian, L.,Costi, M.P.,Luciani, R.,Ferrari, S. (deposition date: 2008-01-18, release date: 2009-01-20, Last modification date: 2023-11-01) |
| Primary citation | Mangani, S.,Cancian, L.,Leone, R.,Pozzi, C.,Lazzari, S.,Luciani, R.,Ferrari, S.,Costi, M.P. Identification of the binding modes of N-phenylphthalimides inhibiting bacterial thymidylate synthase through X-ray crystallography screening J.Med.Chem., 54:5454-5467, 2011 Cited by PubMed Abstract: To identify specific bacterial thymidylate synthase (TS) inhibitors, we exploited phenolphthalein (PTH), which inhibits both bacterial and human enzymes. The X-ray crystal structure of Lactobacillus casei TS (LcTS) that binds PTH showed multiple binding modes of the inhibitor, which prevented a classical structure-based drug design approach. To overcome this issue, we synthesized two phthalimidic libraries that were tested against TS enzymes and then we performed X-ray crystallographic screening of the active compounds. Compounds 6A, 8A, and 12A showed 40-fold higher affinity for bacterial TS than human TS. The X-ray crystallographic screening characterized the binding mode of six inhibitors in complexes with LcTS. Of these, 20A, 23A, and 24A showed a common unique binding mode, whereas 8A showed a different, unique binding mode. A comparative analysis of the LcTS X-ray complexes that were obtained with the pathogenic TS enabled the selection of compounds 8A and 23A as specific compounds and starting points to be exploited for the specific inhibition of pathogen enzymes. PubMed: 21696158DOI: 10.1021/jm2005018 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.6 Å) |
Structure validation
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