5gvl

Plasmodium vivax SHMT bound with PLP-glycine and GS182

spinqualitylabelsall models 5gvl, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5gvl is a 3 chain structure with sequence from Plasmodium vivax Sal-1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.5Å Ligands: CL, GI8, PLG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A5K8L9_PLAVS Publication Abstract from PubMed Target-based approaches toward new antimalarial treatments are highly valuable to prevent resistance development. We report several series of pyrazolopyran-based inhibitors targeting the enzyme serine hydroxymethyltransferase (SHMT), designed to improve microsomal metabolic stability and to identify suitable candidates for in vivo efficacy evaluation. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target assays and PfNF54 strains in cell-based assays with values in the low nanomolar range (3.2-55 nM). A set of carboxylate derivatives demonstrated markedly improved in vitro metabolic stability (t1/2 > 2 h). A selected ligand showed significant in vivo efficacy with 73% of parasitemia reduction in a mouse model. Five new cocrystal structures with PvSHMT were solved at 2.3-2.6 A resolution, revealing a unique water-mediated interaction with Tyr63 at the end of the para-aminobenzoate channel. They also displayed the high degree of conformational flexibility of the Cys364-loop lining this channel. Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures.,Schwertz G, Witschel MC, Rottmann M, Bonnert R, Leartsakulpanich U, Chitnumsub P, Jaruwat A, Ittarat W, Schafer A, Aponte RA, Charman SA, White KL, Kundu A, Sadhukhan S, Lloyd M, Freiberg GM, Srikumaran M, Siggel M, Zwyssig A, Chaiyen P, Diederich F J Med Chem. 2017 Jun 22;60(12):4840-4860. doi: 10.1021/acs.jmedchem.7b00008. Epub, 2017 Jun 13. PMID:28537728 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Serine hydroxymethyltransferase 3D structures

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