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.

4Q0D の概要

• エントリーDOI: 10.2210/pdb4q0d/pdb
• 関連するPDBエントリー: 1QZF 2OIP 3DL5 3DL6 3HJ3 4KY8
• 分子名称: Bifunctional dihydrofolate reductase-thymidylate synthase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 5-FLUORO-2'-DEOXYURIDINE-5'-MONOPHOSPHATE, ... (5 entities in total)
• 機能のキーワード: bifunctional enzyme, transferase, oxidoreductase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Cryptosporidium hominis
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 311009.68

構造登録者

Kumar, V.P.,Anderson, K.S. (登録日: 2014-04-01, 公開日: 2014-10-15, 最終更新日: 2023-09-20)

主引用文献

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

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: 25127103
DOI: 10.1016/j.bmcl.2014.07.049

実験手法

X-RAY DIFFRACTION (3.449 Å)