4KY8

Crystal structure of TS-DHFR from Cryptosporidium hominis in complex with NADPH, methotrexate, FdUMP and 4-((2-amino-6-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)thio)-2-chlorophenyl)-L-glutamic acid

Summary for 4KY8

• Entry DOI: 10.2210/pdb4ky8/pdb
• Related: 1QZF 2OIP 3DL5 3DL6 3HJ3
• Descriptor: Bifunctional thymidylate synthase-dihydrofolate reductase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 5-FLUORO-2'-DEOXYURIDINE-5'-MONOPHOSPHATE, ... (5 entities in total)
• Functional Keywords: bifunctional enzyme, transferase, oxidoreductase, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• Biological source: Cryptosporidium hominis
• Total number of polymer chains: 5
• Total formula weight: 311342.23

Authors

Kumar, V.P.,Anderson, K.S. (deposition date: 2013-05-28, release date: 2013-08-21, Last modification date: 2023-09-20)

Primary citation

Kumar, V.P.,Frey, K.M.,Wang, Y.,Jain, H.K.,Gangjee, A.,Anderson, K.S.
Substituted pyrrolo[2,3-d]pyrimidines as Cryptosporidium hominis thymidylate synthase inhibitors.
Bioorg.Med.Chem.Lett., 23:5426-5428, 2013

PubMed Abstract: Cryptosporidiosis, a gastrointestinal disease caused by a protozoan Cryptosporidium hominis is often fatal in immunocompromised individuals. There is little clinical data to show that the existing treatment by nitazoxanide and paromomycin is effective in immunocompromised individuals. Thymidylate synthase (TS) and dihydrofolate reductase (DHFR) are essential enzymes in the folate biosynthesis pathway and are well established as drug targets in cancer and malaria. A novel series of classical antifolates, 2-amino-4-oxo-5-substituted pyrrolo[2,3-d]pyrimidines have been evaluated as Cryptosporidium hominis thymidylate synthase (ChTS) inhibitors. Crystal structure in complex with the most potent compound, a 2'-chlorophenyl with a sulfur bridge with a Ki of 8.83±0.67 nM is discussed in terms of several Van der Waals, hydrophobic and hydrogen bond interactions with the protein residues and the substrate analog 5-fluorodeoxyuridine monophosphate. Of these interactions, two interactions with the non-conserved residues (A287 and S290) offer an opportunity to develop ChTS specific inhibitors. Compound 6 serves as a lead compound for analog design and its crystal structure provides clues for the design of ChTS specific inhibitors.

PubMed: 23927969
DOI: 10.1016/j.bmcl.2013.07.037

Experimental method

X-RAY DIFFRACTION (3.084 Å)