Structure of the Francisella tularensis enoyl-acyl carrier protein reductase (FabI) in complex with NAD(+) and triclosan.
Acta Crystallogr Sect F Struct Biol Cryst Commun,
PubMed id: 21045289
Enoyl-acyl carrier protein reductase (FabI) catalyzes the last rate-limiting
step in the elongation cycle of the fatty-acid biosynthesis pathway and has been
validated as a potential antimicrobial drug target in Francisella tularensis.
The development of new antibiotic therapies is important both to combat
potential drug-resistant bioweapons and to address the broader societal problem
of increasing antibiotic resistance among many pathogenic bacteria. The crystal
structure of FabI from F. tularensis (FtuFabI) in complex with the inhibitor
triclosan and the cofactor NAD(+) has been solved to a resolution of 2.1 Å.
Triclosan is known to effectively inhibit FabI from different organisms. Precise
characterization of the mode of triclosan binding is required to develop highly
specific inhibitors. Comparison of our structure with the previously determined
FtuFabI structure (PDB code 2jjy) which is bound to only NAD(+) reveals the
conformation of the substrate-binding loop, electron density for which was
missing in the earlier structure, and demonstrates a shift in the conformation
of the NAD(+) cofactor. This shift in the position of the phosphate groups
allows more room in the active site for substrate or inhibitor to bind and be
better accommodated. This information will be crucial for virtual screening
studies to identify novel scaffolds for development into new active inhibitors.