2o7o

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Revision as of 10:57, 21 November 2007

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spinqualitylabelsall models 2o7o, resolution 1.89Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure analysis of TetR(D) complex with doxycycline

Overview

Resistance to the antibiotic tetracycline (Tc) is regulated by its binding, as a Tc:Mg2+ complex to the Tet Repressor protein (TetR). Tc:TetR, recognition is a complex problem, with the protein and ligand each having, several possible conformations and protonation states, which are difficult, to elucidate by experiment alone. We used a combination of free-energy, simulations and crystallographic analysis to investigate the electrostatic, interactions between protein and ligand and the possible role of induced, fit in Tc binding. Tc in solution was described quantum mechanically, while Tc:TetR interactions were described by a recent, high-quality, molecular-mechanics model. The orientations of the amide and imidazole, groups were determined experimentally by a careful analysis of, Debye-Waller factors in alternate crystallographic models. The agreement, with experiment for these orientations suggested that the simulations and, their more detailed, thermodynamic predictions were reliable. We found, that the ligand prefers an extended, zwitterionic state both in solution, and in complexation with the protein. Tc is thus preorganized for binding, while the protein combines lock-and-key behavior for regions close to the, ligand's amide, enolate, and ammonium groups, with an induced fit for, regions close to the Mg2+ ion. These insights and the modeling techniques, employed should be of interest for engineering improved TetR ligands and, improved TetR proteins for gene regulation, as well as for drug design.

About this Structure

2O7O is a Single protein structure of sequence from Escherichia coli with MG, SO4, CL and DXT as ligands. Full crystallographic information is available from OCA.

Reference

Protonation patterns in tetracycline:tet repressor recognition: simulations and experiments., Aleksandrov A, Proft J, Hinrichs W, Simonson T, Chembiochem. 2007 Apr 16;8(6):675-85. PMID:17361981

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