6NJ0

Wild-type E. coli MenE with bound m phenylether-linked analogue of OSB-AMS

Summary for 6NJ0

• Entry DOI: 10.2210/pdb6nj0/pdb
• Descriptor: 2-succinylbenzoate--CoA ligase, 5'-O-{3-[3-(2-carboxyphenyl)-3-oxopropyl]phenyl}adenosine (3 entities in total)
• Functional Keywords: mene, e. coli, menaquinone, ligase
• Biological source: Escherichia coli (strain K12)
• Total number of polymer chains: 1
• Total formula weight: 50755.97

Authors

Si, Y.,Yin, Y.,French, J.B.,Tonge, P.J. (deposition date: 2019-01-02, release date: 2019-04-10, Last modification date: 2024-03-13)

Primary citation

Evans, C.E.,Si, Y.,Matarlo, J.S.,Yin, Y.,French, J.B.,Tonge, P.J.,Tan, D.S.
Structure-Based Design, Synthesis, and Biological Evaluation of Non-Acyl Sulfamate Inhibitors of the Adenylate-Forming Enzyme MenE.
Biochemistry, 58:1918-1930, 2019

PubMed Abstract: N-Acyl sulfamoyladenosines (acyl-AMS) have been used extensively to inhibit adenylate-forming enzymes that are involved in a wide range of biological processes. These acyl-AMS inhibitors are nonhydrolyzable mimics of the cognate acyl adenylate intermediates that are bound tightly by adenylate-forming enzymes. However, the anionic acyl sulfamate moiety presents a pharmacological liability that may be detrimental to cell permeability and pharmacokinetic profiles. We have previously developed the acyl sulfamate OSB-AMS (1) as a potent inhibitor of the adenylate-forming enzyme MenE, an o-succinylbenzoate-CoA (OSB-CoA) synthetase that is required for bacterial menaquinone biosynthesis. Herein, we report the use of computational docking to develop novel, non-acyl sulfamate inhibitors of MenE. A m-phenyl ether-linked analogue (5) was found to be the most potent inhibitor (IC = 8 μM; K = 244 nM), and its X-ray co-crystal structure was determined to characterize its binding mode in comparison to the computational prediction. This work provides a framework for the development of potent non-acyl sulfamate inhibitors of other adenylate-forming enzymes in the future.

PubMed: 30912442
DOI: 10.1021/acs.biochem.9b00003

Experimental method

X-RAY DIFFRACTION (1.83 Å)