6bm7 | pdb_00006bm7

Crystal structure of Trypanosoma brucei AdoMetDC/prozyme heterodimer in complex with pyrimidineamine inhibitor UTSAM568

spinqualitylabelsall models 6bm7, resolution 2.98Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6bm7 is a 6 chain structure with sequence from Tryb2. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: B3P, DY7, PG4, PGE, PUT NonStd Res: PYR Gene: Tb927.6.4410, Tb927.6.4460 (TRYB2) Activity: Adenosylmethionine decarboxylase, with EC number 4.1.1.50 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [DCAMP_TRYBB] Probably has no catalytic activity due to the loss of several residues required for processing and catalysis (PubMed:17485680). Forms a complex with S-adenosylmethionine decarboxylase AdoMetDC which is essential to activate AdoMetDC (PubMed:17485680, PubMed:18949025). Required for the biosynthesis of the polyamine spermidine (PubMed:18949025). Required for growth and survival during the bloodstream life cycle stage (PubMed:18949025). Publication Abstract from PubMed New therapeutic options are needed for treatment of human African trypanosomiasis (HAT) caused by protozoan parasite Trypanosoma brucei. S-Adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme in the polyamine pathway of T. brucei. Previous attempts to target this enzyme were thwarted by the lack of brain penetration of the most advanced series. Herein, we describe a T. brucei AdoMetDC inhibitor series based on a pyrimidineamine pharmacophore that we identified by target-based high-throughput screening. The pyrimidineamines showed selectivity for T. brucei AdoMetDC over the human enzyme, inhibited parasite growth in whole-cell assay, and had good predicted blood-brain barrier penetration. The medicinal chemistry program elucidated structure-activity relationships within the series. Features of the series that were required for binding were revealed by determining the X-ray crystal structure of TbAdoMetDC bound to one analog. The pyrimidineamine series provides a novel starting point for an anti-HAT lead optimization. Species-Selective Pyrimidineamine Inhibitors of Trypanosoma brucei S-Adenosylmethionine Decarboxylase.,Volkov OA, Brockway AJ, Wring SA, Peel M, Chen Z, Phillips MA, De Brabander JK J Med Chem. 2017 Dec 22. doi: 10.1021/acs.jmedchem.7b01654. PMID:29271204 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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