Structure of the Tet repressor-tetracycline complex and regulation of antibiotic resistance
Abstract
The most frequently occurring resistance of Gram-negative bacteria against tetracyclines is triggered by drug recognition of the Tet repressor. This causes dissociation of the repressor-operator DNA complex and enables expression of the resistance protein TetA, which is responsible for active efflux of tetracycline. The 2.5 angstrom resolution crystal structure of the homodimeric Tet repressor complexed with tetracycline-magnesium reveals detailed drug recognition. The orientation of the operator-binding helix-turn-helix motifs of the repressor is inverted in comparison with other DNA binding proteins. The repressor-drug complex is unable to interact with DNA because the separation of the DNA binding motifs is 5 angstroms wider than usually observed.
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The magnesium ion found in the tetracycline complex is in an identical position relative to tetracycline as in the structure of its complex with a class D tet-repressor, where it is also required for function.
“and is found here in an identical position relative to Tc as in the structure of its complex with a class D tet-repressor, where it is also required for function (Hinrichs et al. 1994”
From The Structural Basis for the Action of the Antibiotics Tetracycline, Pactamycin, and Hygromycin B on the 30S Ribosomal Subunit (2000) · cites this paper as Hinrichs et al. 1994
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The crisis in antibiotic resistance
Neu, H. C. (1992) · Science · doi:10.1126/science.257.5073.1064 · Cited by 2,834 · see citing works
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Brodersen, D. E., Clemons, W. M., Carter, A. P., Morgan-Warren, R. J., Wimberly, B. T., & Ramakrishnan, V. (2000) · Cell · doi:10.1016/s0092-8674(00)00216-6 · Cited by 950 · see citing works
“…and is found here in an identical position relative to Tc as in the structure the subunit, in close proximity to H44 and sandwiched between the functionally important H27 in the central of its complex with a class D tet-repressor, where it is also required for function (Hinrichs et al., 1994).”
BackgroundTetracyclines: Antibiotic action, uptake, and resistance mechanisms
Schnappinger, D., & Hillen, W. (1996) · Archives of Microbiology · doi:10.1007/s002030050339 · Cited by 484 · see citing works
Self-citationRegulation of bacterial drug export systems
Grkovic, S., Brown, M. H., & Skurray, R. A. (2002) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.66.4.671-701.2002 · Cited by 423 · see citing works
Optimization of the Tet-On system for regulated gene expression through viral evolution
Zhou, X., Vink, M., Klaver, B., Berkhout, B., & Das, A. T. (2006) · Gene Therapy · doi:10.1038/sj.gt.3302780 · Cited by 224 · see citing works
- Authors
- Hinrichs, W., Kisker, C., Düvel, M., Müller, A., Tovar, K., Hillen, W., & Saenger, W.
- Affiliations
- Freie Universität Berlin (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Venue
- Science
- Published
- 1994-04-15
- Volume
- 264
- Issue
- 5157
- Pages
- 418-420
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2092652351
- Cited by
- 408
- References
- 1
- Citations by year
- 2026: 10 · 2025: 3 · 2024: 12 · 2023: 11 · 2022: 13 · 2021: 13 · 2020: 12 · 2019: 3 · 2018: 15 · 2017: 11 · 2016: 8 · 2015: 7 · 2014: 13 · 2013: 10 · 2012: 5
- FWCI
- 8.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Desy Publications Database (Deutsches Elektronen-Synchrotron DESY) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- Tet repressor, tetracycline, tetracycline resistance, Gram-negative bacteria, drug identification, helix-turn-helix motif, DNA binding, repressor-operator complex, magnesium complexes, crystal structure, antibiotic resistance regulation
- MeSH terms
- Bacterial Proteins, DNA, Bacterial, Hydrogen Bonding, Magnesium, Models, Molecular, Mutation, Operator Regions, Genetic, Protein Conformation, Repressor Proteins, Tetracycline, Tetracycline Resistance, Protein Structure, Secondary, Protein Folding, Antiporters, Helix-Loop-Helix Motifs, Crystallography, X-Ray
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