3BNZ

Crystal structure of Thymidylate Synthase ternary complex with dUMP and 8A inhibitor

Summary for 3BNZ

• Entry DOI: 10.2210/pdb3bnz/pdb
• Related: 1LCA
• Descriptor: Thymidylate synthase, PHOSPHATE ION, 2'-DEOXYURIDINE 5'-MONOPHOSPHATE, ... (5 entities in total)
• Functional Keywords: thymidylate synthase, methyltransferase, nucleotide biosynthesis, transferase
• Biological source: Lactobacillus casei
• Cellular location: Cytoplasm: P00469
• Total number of polymer chains: 1
• Total formula weight: 37295.87

Authors

Leone, R.,Cancian, L.,Luciani, R.,Ferrari, S.,Costi, M.P.,Mangani, S. (deposition date: 2007-12-15, release date: 2008-12-16, 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

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: 21696158
DOI: 10.1021/jm2005018

Experimental method

X-RAY DIFFRACTION (2.6 Å)