Abstract:Durch den übermäßigen Gebrauch von Antibiotika haben Bakterien Resistenzen erworben, die unterschiedlichen Mechanismen folgen. Die bakteriostatische Wirkung des Breitbandantibiotikums Tetracyclin (Tc) beruht auf der Inaktivierung der bakteriellen Ribosomen, sodass die Proteinbiosynthese unterbrochen wird und die Bakterien absterben. Der in Gram‐negativen Bakterien am häufigsten vorkommende Resistenzmechanismus gegen Tc beruht auf dem membranständigen Protein TetA, das eingedrungenes Tc aus der Bakterienzelle e… Show more
“…When tetracycline enters the bacterial cell, it forms a chelate complex with divalent metal ions, mostly Mg 2+ . Under physiological conditions, the metal cation is chelated by the deprotonated 1,3-keto−enol group O11/O12 - of the zwitteranionic tetracycline molecule (Chart ). − 1 Structure of the Physiologically Active Tetracycline−Magnesium Complex 1-3 a a The red line shows the orientation of the transition dipole of the first intense absorption in the BCD chromophore. …”
Section: Introductionmentioning
confidence: 99%
“…Two molecules of the [TcMg] + complex bind to the TetR binding sites. This induces a cascade of allosteric conformational changes in the TetR protein, which result in an increased center-to-center separation of the DNA-recognition helices (from 36.6 Å in the operator complex to 39.6 Å after inducer binding). − These conformational changes lead to the dissociation of the TetR/DNA complex.…”
We present a computational model study designed to simulate the results of time-resolved fluorescence spectra of tryptophan in proteins. In such measurements, the occurrence of more than one fluorescence lifetime is generally attributed to the existence of several tryptophan rotamers and/or structural conformations of the protein structure. The protein system we chose for this initial study is the tetracycline repressor (TetR), an interesting model system for the investigation of the mechanisms of transcriptional regulation. Fluorescence resonance energy transfer (FRET) from tryptophan to tetracycline is frequently observed in complexes of the TetR with the antibiotic tetracycline. We use a combined classical/quantum mechanical approach to model the structure and the spectroscopic properties of the TetR-tetracycline complex. A classical molecular dynamics simulation provides input geometries for semiempirical quantum mechanical/molecular mechanical (QM/MM) single-point configuration interaction (CI) calculations, which are used to calculate tryptophan vertical absorption and fluorescence energies and intensities as well as relative FRET rate constants. These rate constants together with the Einstein coefficients for spontaneous emission and an assumed rate for nonradiative deactivation allow us to simulate fluorescence decay curves with and without FRET and for the entire ensemble as well as for individual rotamers. Our results indicate that the classical "rotamer model", used to explain the multiexponential fluorescence-decay curves of time-resolved tryptophan emission spectra, can be extended to systems with FRET acceptors present in the protein matrix but that the interpretation of the fitted lifetimes is different to that usually used.
“…When tetracycline enters the bacterial cell, it forms a chelate complex with divalent metal ions, mostly Mg 2+ . Under physiological conditions, the metal cation is chelated by the deprotonated 1,3-keto−enol group O11/O12 - of the zwitteranionic tetracycline molecule (Chart ). − 1 Structure of the Physiologically Active Tetracycline−Magnesium Complex 1-3 a a The red line shows the orientation of the transition dipole of the first intense absorption in the BCD chromophore. …”
Section: Introductionmentioning
confidence: 99%
“…Two molecules of the [TcMg] + complex bind to the TetR binding sites. This induces a cascade of allosteric conformational changes in the TetR protein, which result in an increased center-to-center separation of the DNA-recognition helices (from 36.6 Å in the operator complex to 39.6 Å after inducer binding). − These conformational changes lead to the dissociation of the TetR/DNA complex.…”
We present a computational model study designed to simulate the results of time-resolved fluorescence spectra of tryptophan in proteins. In such measurements, the occurrence of more than one fluorescence lifetime is generally attributed to the existence of several tryptophan rotamers and/or structural conformations of the protein structure. The protein system we chose for this initial study is the tetracycline repressor (TetR), an interesting model system for the investigation of the mechanisms of transcriptional regulation. Fluorescence resonance energy transfer (FRET) from tryptophan to tetracycline is frequently observed in complexes of the TetR with the antibiotic tetracycline. We use a combined classical/quantum mechanical approach to model the structure and the spectroscopic properties of the TetR-tetracycline complex. A classical molecular dynamics simulation provides input geometries for semiempirical quantum mechanical/molecular mechanical (QM/MM) single-point configuration interaction (CI) calculations, which are used to calculate tryptophan vertical absorption and fluorescence energies and intensities as well as relative FRET rate constants. These rate constants together with the Einstein coefficients for spontaneous emission and an assumed rate for nonradiative deactivation allow us to simulate fluorescence decay curves with and without FRET and for the entire ensemble as well as for individual rotamers. Our results indicate that the classical "rotamer model", used to explain the multiexponential fluorescence-decay curves of time-resolved tryptophan emission spectra, can be extended to systems with FRET acceptors present in the protein matrix but that the interpretation of the fitted lifetimes is different to that usually used.
“…Saenger's research includes the study of hydrogen bonding, cyclodextrin inclusion compounds, enzymes, nucleic acids, proteins, and photosynthesis. His Review on the tetracycline repressor as a paradigm for a biological switch appeared in 2000 in Angewandte Chemie 1…”
Section: Crystallographers Honor W Saengermentioning
“…Atc shows reduced antibacterial activity compared to tetracycline but binds to the tetracycline repressor protein (TetR) about 500 times more strongly than the parent compound 4 and induces the tetracycline repressor system about 24 times more efficiently than tetracycline. 5 This characteristic is important in view of the interest in tetracyclines as "gene switches" 6 that arises from the regulatory function of TetR in the expression of the tetracycline antiporter protein, which actively transports tetracyclines from within resistant bacteria. 7 A further fascinating aspect of Atc is that it is able to bind to TetR without a complexed Mg 2+ ion, 5 which is necessary for tetracycline to bind.…”
Ab initio and density functional theory (DFT) calculations have been used to investigate the conformations and tautomeric forms of neutral anhydrotetracycline in aqueous solution.
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