Structure of the Francisella tularensis enoyl-acyl carrier protein reductase (FabI) in complex with NAD+ and triclosan.pdf (570.72 kB)

Structure of the Francisella tularensis enoyl-acyl carrier protein reductase (FabI) in complex with NAD plus and triclosan

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journal contribution
posted on 27.05.2011 by Shahila Mehboob, Kent Truong, Bernard D. Santarsiero, Michael E. Johnson
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 A. 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.

Funding

This work was supported by National Institutes of Health Grant U01 AI077949. Data were collected on the Southeast Regional Collaborative Access Team (SER-CAT) 22-BM beamline at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. W-31-109-Eng-38.

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Publisher Statement

The original publication is available through the International Union of Crystallography at DOI: 10.1107/S1744309110039862.

Publisher

International Union of Crystallography

Language

en_US

issn

1744-3091

Issue date

01/11/2010

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