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Putative dioxygen-binding sites and recognition of tigecycline and minocycline in the tetracycline-degrading monooxygenase TetX.
- Source :
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Acta Crystallographica: Section D (Wiley-Blackwell) . Sep2013, Vol. 69 Issue 9, p1758-1767. 10p. - Publication Year :
- 2013
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Abstract
- Expression of the aromatic hydroxylase TetX under aerobic conditions confers bacterial resistance against tetracycline antibiotics. Hydroxylation inactivates and degrades tetracyclines, preventing inhibition of the prokaryotic ribosome. X-ray crystal structure analyses of TetX in complex with the second-generation and third-generation tetracyclines minocycline and tigecycline at 2.18 and 2.30 Å resolution, respectively, explain why both clinically potent antibiotics are suitable substrates. Both tetracyclines bind in a large tunnel-shaped active site in close contact to the cofactor FAD, pre-oriented for regioselective hydroxylation to 11a-hydroxytetracyclines. The characteristic bulky 9- tert-butylglycylamido substituent of tigecycline is solvent-exposed and does not interfere with TetX binding. In the TetX-minocycline complex a second binding site for a minocycline dimer is observed close to the active-site entrance. The pocket is formed by the crystal packing arrangement on the surface of two neighbouring TetX monomers. Crystal structure analysis at 2.73 Å resolution of xenon-pressurized TetX identified two adjacent Xe-binding sites. These putative dioxygen-binding cavities are located in the substrate-binding domain next to the active site. Molecular-dynamics simulations were performed in order to characterize dioxygen-diffusion pathways to FADH2 at the active site. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 09074449
- Volume :
- 69
- Issue :
- 9
- Database :
- Academic Search Index
- Journal :
- Acta Crystallographica: Section D (Wiley-Blackwell)
- Publication Type :
- Academic Journal
- Accession number :
- 90481739
- Full Text :
- https://doi.org/10.1107/S0907444913013802