4a6n | pdb_00004a6n
STRUCTURE OF THE TETRACYCLINE DEGRADING MONOOXYGENASE TETX IN COMPLEX WITH TIGECYCLINE
Structural highlights
FunctionTETX_BACT4 An FAD-requiring monooxygenase active on tetracycline antibiotic derivatives, which leads to their inactivation (PubMed:15452119, PubMed:16128584). Hydroxylates carbon 11a of oxytetracycline and tigecycline (PubMed:15452119, PubMed:26097034). Acts on many tetracycline analogs (chlorotetracycline, demeclocycline, doxycycline, minocycline, oxytetracyclinee), probably by monooxygenization (PubMed:15452119, PubMed:16128584). Tigecycline, a new generation tetracycline antibiotic, is rendered less effective against E.coli by this monooxygenation, is much weaker at inhibiting translation in vitro and binds Mg(2+) considerably less well (PubMed:16128584, PubMed:26097034). Expression in E.coli BW25113 reduces its growth rate about 5%. The reaction probably proceeds by FAD reduction by NADPH and, second, hydroxylation of antibiotic in a ping-pong mechanism (PubMed:23236139). Degrades chlortetracycline, probably by monooxygenation (PubMed:15452119, PubMed:28481346). Slowly oxidizes anhydrotetracycline, the final substrate in tetracycline biosynthesis (PubMed:26097034).[HAMAP-Rule:MF_00845][1] [2] [3] [4] [5] Publication Abstract from PubMedExpression 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 A 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 A 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. Putative dioxygen-binding sites and recognition of tigecycline and minocycline in the tetracycline-degrading monooxygenase TetX.,Volkers G, Damas JM, Palm GJ, Panjikar S, Soares CM, Hinrichs W Acta Crystallogr D Biol Crystallogr. 2013 Sep 1;69(Pt 9):1758-67. doi:, 10.1107/S0907444913013802. Epub 2013 Aug 15. PMID:23999299[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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