3U16
Structure of BasE N-terminal domain from Acinetobacter baumannii bound to 6-(p-benzyloxy)phenyl-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid.
Summary for 3U16
| Entry DOI | 10.2210/pdb3u16/pdb |
| Related | 3O82 3O83 3O84 3U17 |
| Descriptor | Peptide arylation enzyme, 6-[4-(benzyloxy)phenyl]-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid, CALCIUM ION, ... (6 entities in total) |
| Functional Keywords | anl superfamily, adenylating enzyme, 2, 3-dihydroxybenzoate:aryl carrier protein ligase, basf, ligase |
| Biological source | Acinetobacter baumannii |
| Total number of polymer chains | 2 |
| Total formula weight | 123086.28 |
| Authors | Gulick, A.M.,Drake, E.J.,Aldrich, C.C.,Neres, J. (deposition date: 2011-09-29, release date: 2012-10-03, Last modification date: 2023-09-13) |
| Primary citation | Neres, J.,Engelhart, C.A.,Drake, E.J.,Wilson, D.J.,Fu, P.,Boshoff, H.I.,Barry 3rd, C.E.,Gulick, A.M.,Aldrich, C.C. Non-nucleoside inhibitors of BasE, an adenylating enzyme in the siderophore biosynthetic pathway of the opportunistic pathogen Acinetobacter baumannii. J.Med.Chem., 56:2385-2405, 2013 Cited by PubMed Abstract: Siderophores are small-molecule iron chelators produced by bacteria and other microorganisms for survival under iron limiting conditions such as found in a mammalian host. Siderophore biosynthesis is essential for the virulence of many important Gram-negative pathogens including Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli. We performed high-throughput screening against BasE, which is involved in siderophore biosynthesis in A. baumannii, and identified 6-phenyl-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid 15. Herein we report the synthesis, biochemical, and microbiological evaluation of a systematic series of analogues of the HTS hit 15. Analogue 67 is the most potent analogue with a KD of 2 nM against BasE. Structural characterization of the inhibitors with BasE reveals that they bind in a unique orientation in the active site, occupying all three substrate binding sites, and thus can be considered as multisubstrate inhibitors. These results provide a foundation for future studies aimed at increasing both enzyme potency and antibacterial activity. PubMed: 23437866DOI: 10.1021/jm301709s PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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