ATP binding enables broad antibiotic selectivity of aminoglycoside phosphotransferase(3')-IIIa: an elastic network analysis.

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Wieninger SA, Serpersu EH, Ullmann GM

ATP binding enables broad antibiotic selectivity of aminoglycoside phosphotransferase(3')-IIIa: an elastic network analysis.

J Mol Biol. 2011 Jun 10;409(3):450-65. doi: 10.1016/j.jmb.2011.03.061. Epub 2011 Apr 6.

PubMed ID

21477597 [ View in PubMed

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Abstract

The bacterial enzyme aminoglycoside phosphotransferase(3')-IIIa (APH) confers resistance against a wide range of aminoglycoside antibiotics. In this study, we use the Gaussian network model to investigate how the binding of nucleotides and antibiotics influences the dynamics and thereby the ligand binding properties of APH. Interestingly, in NMR experiments, the dynamics differ significantly in various APH complexes, although crystallographic studies indicate that no larger conformational changes occur upon ligand binding. Isothermal titration calorimetry also shows different thermodynamic contributions to ligand binding. Formation of aminoglycoside-APH complexes is enthalpically driven, while the enthalpic change upon aminoglycoside binding to the nucleotide-APH complex is much smaller. The differential effects of nucleotide binding and antibiotic binding to APH can be explained theoretically by single-residue fluctuations and correlated motions of the enzyme. The surprising destabilization of beta-sheet residues upon nucleotide binding, as seen in hydrogen/deuterium exchange experiments, shows that the number of closest neighbors does not fully explain residue flexibility. Additionally, we must consider correlated motions of dynamic protein domains, which show that not only connectivity but also the overall protein architecture is important for protein dynamics.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Kanamycin	Aminoglycoside 3'-phosphotransferase	Protein	Escherichia coli	Unknown	Substrate	Details