3U17

Structure of BasE N-terminal domain from Acinetobacter baumannii bound to 6-(p-benzoyl)phenyl-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

Summary for 3U17

• Entry DOI: 10.2210/pdb3u17/pdb
• Related: 3O82 3O83 3O84 3U16
• Descriptor: Peptide arylation enzyme, 6-(4-benzoylphenyl)-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: 123122.33

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

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: 23437866
DOI: 10.1021/jm301709s

Experimental method

X-RAY DIFFRACTION (2.1 Å)