3UIC

Crystal Structure of FabI, an Enoyl Reductase from F. tularensis, in complex with a Novel and Potent Inhibitor

Summary for 3UIC

• Entry DOI: 10.2210/pdb3uic/pdb
• Descriptor: Enoyl-[acyl-carrier-protein] reductase [NADH], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 1-(3,4-dichlorobenzyl)-5,6-dimethyl-1H-benzimidazole, ... (4 entities in total)
• Functional Keywords: rossmann fold, enoyl reductase, nadh binding, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Francisella tularensis subsp. tularensis
• Total number of polymer chains: 16
• Total formula weight: 495603.01

Authors

Mehboob, S.,Santarsiero, B.D.,Truong, K.,Johnson, M.E. (deposition date: 2011-11-04, release date: 2012-06-06, Last modification date: 2023-09-13)

Primary citation

Mehboob, S.,Hevener, K.E.,Truong, K.,Boci, T.,Santarsiero, B.D.,Johnson, M.E.
Structural and enzymatic analyses reveal the binding mode of a novel series of Francisella tularensis enoyl reductase (FabI) inhibitors.
J.Med.Chem., 55:5933-5941, 2012

PubMed Abstract: Because of structural and mechanistic differences between eukaryotic and prokaryotic fatty acid synthesis enzymes, the bacterial pathway, FAS-II, is an attractive target for the design of antimicrobial agents. We have previously reported the identification of a novel series of benzimidazole compounds with particularly good antibacterial effect against Francisella tularensis, a Category A biowarfare pathogen. Herein we report the crystal structure of the F. tularensis FabI enzyme in complex with our most active benzimidazole compound bound with NADH. The structure reveals that the benzimidazole compounds bind to the substrate site in a unique conformation that is distinct from the binding motif of other known FabI inhibitors. Detailed inhibition kinetics have confirmed that the compounds possess a novel inhibitory mechanism that is unique among known FabI inhibitors. These studies could have a strong impact on future antimicrobial design efforts and may reveal new avenues for the design of FAS-II active antibacterial compounds.

PubMed: 22642319
DOI: 10.1021/jm300489v

Experimental method

X-RAY DIFFRACTION (2.5 Å)