7fgw

Toxoplasma gondii dihydrofolate reductase thymidylate synthase (TgDHFR-TS) complexed with pyrimethamine, NADPH and dUMP

spinqualitylabelsall models 7fgw, resolution 2.15Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7fgw is a 4 chain structure with sequence from Toxoplasma gondii. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.15Å Ligands: BEN, CP6, NDP, UMP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DRTS_TOXGO Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, DNA precursor synthesis, and for the conversion of dUMP to dTMP (By similarity). 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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