7xi7

Human dihydrofolate reductase complexed with P39

spinqualitylabelsall models 7xi7, resolution 1.65Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7xi7 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.65Å Ligands: 4RI, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease DYR_HUMAN Defects in DHFR are the cause of megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:613839. DHFRD is an inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms. Function DYR_HUMAN Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1. Publication Abstract from PubMed Pyrimethamine (Pyr), a known dihydrofolate reductase (DHFR) inhibitor, has long been used to treat toxoplasmosis caused by Toxoplasma gondii (Tg) infection. However, Pyr is effective only at high doses with associated toxicity to patients, calling for safer alternative treatments. In this study, we investigated a series of Pyr analogues, previously developed as DHFR inhibitors of Plasmodium falciparum bifunctional DHFR-thymidylate synthase (PfDHFR-TS), for their activity against T. gondii DHFR-TS (TgDHFR-TS). Of these, a set of compounds with a substitution at the C(6) position of the pyrimidine ring exhibited high binding affinities (in a low nanomolar range) against TgDHFR-TS and in vitro T. gondii inhibitory activity. Three-dimensional structures of TgDHFR-TS reported here include the ternary complexes with Pyr, P39, or P40. A comparison of these structures showed the minor steric strain between the p-chlorophenyl group of Pyr and Thr83 of TgDHFR-TS. Such a conflict was relieved in the complexes with the two analogues, P39 and P40, explaining their highest binding affinities described herein. Moreover, these structures suggested that the hydrophobic environment in the active-site pocket could be used for drug design to increase the potency and selectivity of antifolate inhibitors. These findings would accelerate the development of new antifolate drugs to treat toxoplasmosis. Structural Insight into Effective Inhibitors' Binding to Toxoplasma gondii Dihydrofolate Reductase Thymidylate Synthase.,Vanichtanankul J, Yoomuang A, Taweechai S, Saeyang T, Pengon J, Yuvaniyama J, Tarnchompoo B, Yuthavong Y, Kamchonwongpaisan S ACS Chem Biol. 2022 Jun 17. doi: 10.1021/acschembio.1c00627. PMID:35715223 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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