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| {{STRUCTURE_2o7o| PDB=2o7o | SCENE= }} | | {{STRUCTURE_2o7o| PDB=2o7o | SCENE= }} |
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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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| ==Overview==
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| 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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_17361981}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 17361981 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_17361981}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Helix-turn-helix]] | | [[Category: Helix-turn-helix]] |
| [[Category: Metal coordination]] | | [[Category: Metal coordination]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 10:25:28 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 11:49:57 2008'' |