2o7o
From Proteopedia
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'''Crystal structure analysis of TetR(D) complex with doxycycline''' | '''Crystal structure analysis of TetR(D) complex with doxycycline''' | ||
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[[Category: Hinrichs, W.]] | [[Category: Hinrichs, W.]] | ||
[[Category: Proft, J.]] | [[Category: Proft, J.]] | ||
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Revision as of 07:25, 4 May 2008
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. 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 Page seeded by OCA on Sun May 4 10:25:28 2008
