5zh2

CRYSTAL STRUCTURE OF PfKRS WITH INHIBITOR CLADO-5

spinqualitylabelsall models 5zh2, resolution 2.66Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5zh2 is a 2 chain structure with sequence from Plasmodium falciparum NF54. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.66Å Ligands: 9CU, CL, LYS, MPO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function W7JP72_PLAFO Publication Abstract from PubMed The dependence of drug potency on diastereomeric configurations is a key facet. Using a novel general divergent synthetic route for a three-chiral center antimalarial natural product cladosporin, we built its complete library of stereoisomers (cladologs) and assessed their inhibitory potential using parasite-, enzyme-, and structure-based assays. We show that potency is manifest via tetrahyropyran ring conformations that are housed in the ribose binding pocket of parasite lysyl tRNA synthetase (KRS). Strikingly, drug potency between top and worst enantiomers varied 500-fold, and structures of KRS-cladolog complexes reveal that alterations at C3 and C10 are detrimental to drug potency whereas changes at C3 are sensed by rotameric flipping of glutamate 332. Given that scores of antimalarial and anti-infective drugs contain chiral centers, this work provides a new foundation for focusing on inhibitor stereochemistry as a facet of antimicrobial drug development. Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite.,Das P, Babbar P, Malhotra N, Sharma M, Jachak GR, Gonnade RG, Shanmugam D, Harlos K, Yogavel M, Sharma A, Reddy DS J Med Chem. 2018 Jun 4. doi: 10.1021/acs.jmedchem.8b00565. PMID:29779382 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Aminoacyl tRNA synthetase 3D structures

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