4a99

From Proteopedia

Jump to: navigation, search

STRUCTURE OF THE TETRACYCLINE DEGRADING MONOOXYGENASE TETX IN COMPLEX WITH MINOCYCLINE

Structural highlights

4a99 is a 4 chain structure with sequence from Bacteroides thetaiotaomicron. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.18Å
Ligands:FAD, MIY, SO4
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TETX_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 PubMed

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 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.

Loading citation details..
Citations
3 reviews cite this structure
Tetracycline-Inactivating Enzymes.
Markley et al. (2018)
2 more
13 other articles
No citations found

References

  1. ↑ Yang W, Moore IF, Koteva KP, Bareich DC, Hughes DW, Wright GD. TetX is a flavin-dependent monooxygenase conferring resistance to tetracycline antibiotics. J Biol Chem. 2004 Dec 10;279(50):52346-52. doi: 10.1074/jbc.M409573200. Epub 2004, Sep 27. PMID:15452119 doi:http://dx.doi.org/10.1074/jbc.M409573200
  2. ↑ Moore IF, Hughes DW, Wright GD. Tigecycline is modified by the flavin-dependent monooxygenase TetX. Biochemistry. 2005 Sep 6;44(35):11829-35. doi: 10.1021/bi0506066. PMID:16128584 doi:http://dx.doi.org/10.1021/bi0506066
  3. ↑ Walkiewicz K, Benitez Cardenas AS, Sun C, Bacorn C, Saxer G, Shamoo Y. Small changes in enzyme function can lead to surprisingly large fitness effects during adaptive evolution of antibiotic resistance. Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):21408-13. doi:, 10.1073/pnas.1209335110. Epub 2012 Dec 10. PMID:23236139 doi:http://dx.doi.org/10.1073/pnas.1209335110
  4. ↑ Forsberg KJ, Patel S, Wencewicz TA, Dantas G. The Tetracycline Destructases: A Novel Family of Tetracycline-Inactivating Enzymes. Chem Biol. 2015 Jul 23;22(7):888-97. doi: 10.1016/j.chembiol.2015.05.017. Epub, 2015 Jun 18. PMID:26097034 doi:http://dx.doi.org/10.1016/j.chembiol.2015.05.017
  5. ↑ Park J, Gasparrini AJ, Reck MR, Symister CT, Elliott JL, Vogel JP, Wencewicz TA, Dantas G, Tolia NH. Plasticity, dynamics, and inhibition of emerging tetracycline resistance enzymes. Nat Chem Biol. 2017 May 8. doi: 10.1038/nchembio.2376. PMID:28481346 doi:http://dx.doi.org/10.1038/nchembio.2376
  6. ↑ Volkers G, Damas JM, Palm GJ, Panjikar S, Soares CM, Hinrichs W. Putative dioxygen-binding sites and recognition of tigecycline and minocycline in the tetracycline-degrading monooxygenase TetX. Acta Crystallogr D Biol Crystallogr. 2013 Sep 1;69(Pt 9):1758-67. doi:, 10.1107/S0907444913013802. Epub 2013 Aug 15. PMID:23999299 doi:10.1107/S0907444913013802

Contents


PDB ID 4a99

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://proteopedia.org/wiki/index.php/4a99"
Personal tools