4ky4

Crystal structure of non-classical TS inhibitor 2 in complex with Toxoplasma gondii TS-DHFR

spinqualitylabelsall models 4ky4, resolution 2.79Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ky4 is a 8 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 2.79Å Ligands: 04J, 1UE, 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 Infection by the parasite Toxoplasma gondii (tg) can lead to toxoplasmosis in immunocompromised patients such as organ transplant, cancer and HIV/AIDS patients. The bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) enzyme is crucial for nucleotide synthesis in T. gondii, and represents a potential target to combat T. gondii infection. While species selectivity with drugs has been attained for DHFR, TS is much more conserved across species and specificity is significantly more challenging. We discovered novel substituted-9H-pyrimido[4,5-b]indoles 1-3 with single-digit nanomolar Ki for tgTS, two of which, 2 and 3, are 28- and 122-fold selective over human TS (hTS). The synthesis of these compounds, and their structures in complex with tgTS-DHFR are presented along with binding measurements and cell culture data. These results show, for the very first time, that in spite of the high degree of conservation of active site residues between hTS and the parasite TS, specificity has been accomplished via novel structures and provides a new target (TS) for selective drug development against parasitic infections. Discovery of potent and selective inhibitors of thymidylate synthase for opportunistic infections.,Zaware N, Sharma H, Yang J, Devambatla RK, Queener SF, Anderson KS, Gangjee A ACS Med Chem Lett. 2013 Oct 4;4(12):1148-1151. PMID:24470841 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dihydrofolate reductase 3D structures

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