title: Recognition of drug degradation products by target proteins: isotetracycline binding to Tet repressor.
abstract: Tetracycline antibiotics and their degradation products appear in medically treated tissues, food, soil, and manure sludge in the environment. In the context of protein interactions with various tetracyclines we performed crystal structure analyses of the tetracycline repressor in complex with weak or noninducing tetracycline derivatives. Isotetracyclines are degradation products of tetracyclines, which occur under physiological conditions. The typical framework of the antibiotic is irreversibly broken at the BC-ring connection, leading to a modified orientation of the AB to the new C*D ring fragments. The shape of the zwitterionic AB-ring fragment is unchanged and still binds to the TetR recognition site in a manner comparable to the intact antibiotic but without typical Mg(2+) chelation. This work is an example that drug degradation products can still bind to specific targets and should be discussed in light of potential and critical side effects.
authors.affiliation: Department of Molecular Structural Biology, Institute for Biochemistry, University of Greifswald, Felix-Hausdorff-Strasse 4, D-17489 Greifswald, Germany.
authors.forename: Gesa
authors.initials: G
authors.lastname: Volkers
authors.forename: Lothar
authors.initials: L
authors.lastname: Petruschka
authors.forename: Winfried
authors.initials: W
authors.lastname: Hinrichs
mesh_terms: D000494:Allosteric Regulation; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry; D012097:Repressor Proteins / Q000737:chemistry*; D020349:Surface Plasmon Resonance; D013753:Tetracycline Resistance; D013754:Tetracyclines / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D011994:Recombinant Proteins; D012097:Repressor Proteins; D013754:Tetracyclines; C034811:tetracycline resistance-encoding transposon repressor protein