4Q0D
Crystal structure of TS-DHFR from Cryptosporidium hominis in complex with NADPH, FdUMP, methotrexate and 2-amino-4-oxo-4,7-dihydro-pyrrolo[2,3-d]pyrimidine-methyl-phenyl-L-glutamic acid.
Summary for 4Q0D
| Entry DOI | 10.2210/pdb4q0d/pdb |
| Related | 1QZF 2OIP 3DL5 3DL6 3HJ3 4KY8 |
| Descriptor | Bifunctional dihydrofolate reductase-thymidylate synthase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 5-FLUORO-2'-DEOXYURIDINE-5'-MONOPHOSPHATE, ... (5 entities in total) |
| Functional Keywords | bifunctional enzyme, transferase, oxidoreductase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Cryptosporidium hominis |
| Total number of polymer chains | 5 |
| Total formula weight | 311009.68 |
| Authors | Kumar, V.P.,Anderson, K.S. (deposition date: 2014-04-01, release date: 2014-10-15, Last modification date: 2023-09-20) |
| Primary citation | Kumar, V.P.,Cisneros, J.A.,Frey, K.M.,Castellanos-Gonzalez, A.,Wang, Y.,Gangjee, A.,White, A.C.,Jorgensen, W.L.,Anderson, K.S. Structural studies provide clues for analog design of specific inhibitors of Cryptosporidium hominis thymidylate synthase-dihydrofolate reductase. Bioorg.Med.Chem.Lett., 24:4158-4161, 2014 Cited by PubMed Abstract: Cryptosporidium is the causative agent of a gastrointestinal disease, cryptosporidiosis, which is often fatal in immunocompromised individuals and children. Thymidylate synthase (TS) and dihydrofolate reductase (DHFR) are essential enzymes in the folate biosynthesis pathway and are well established as drug targets in cancer, bacterial infections, and malaria. Cryptosporidium hominis has a bifunctional thymidylate synthase and dihydrofolate reductase enzyme, compared to separate enzymes in the host. We evaluated lead compound 1 from a novel series of antifolates, 2-amino-4-oxo-5-substituted pyrrolo[2,3-d]pyrimidines as an inhibitor of Cryptosporidium hominis thymidylate synthase with selectivity over the human enzyme. Complementing the enzyme inhibition compound 1 also has anti-cryptosporidial activity in cell culture. A crystal structure with compound 1 bound to the TS active site 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 (TS), cofactor NADPH and inhibitor methotrexate (DHFR). Another crystal structure in complex with compound 1 bound in both the TS and DHFR active sites is also reported here. The crystal structures provide clues for analog design and for the design of ChTS-DHFR specific inhibitors. PubMed: 25127103DOI: 10.1016/j.bmcl.2014.07.049 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.449 Å) |
Structure validation
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