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Analyzing DNA-Protein Interactions with Streptavidin-Based Biolayer Interferometry
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Structural Basis for DNA Gyrase Interaction with Coumermycin A1.
Arnaud Vanden Broeck1, Alastair G McEwen1, Yassmine Chebaro1
1Integrated Structural Biology Department, IGBMC, UMR7104 CNRS, U1258 Inserm, University of Strasbourg, Illkirch 67404 , France.
Journal of Medicinal Chemistry
|March 29, 2019
Summary
Coumermycin A1, an antibiotic, binds to bacterial DNA gyrase, inhibiting its function. This study reveals how coumermycin A1 traps two ATP sites, offering new avenues for antibiotic development.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Coumermycin A1 is a natural aminocoumarin with antibacterial properties.
- It targets bacterial DNA gyrase, a crucial enzyme in DNA replication.
- DNA gyrase belongs to the GHKL proteins superfamily.
Purpose of the Study:
- To determine the cocrystal structures of gyrase B bound to coumermycin A1.
- To elucidate the mechanism of coumermycin A1 inhibition of DNA gyrase.
- To provide a structural basis for developing new coumermycin A1 derivatives.
Main Methods:
- X-ray crystallography to obtain cocrystal structures.
- Biochemical assays to study enzyme inhibition.
- Comparative structural analysis across different species.
Main Results:
- The first cocrystal structures of gyrase B with coumermycin A1 were determined.
- One coumermycin A1 molecule was observed to bind and trap two ATP-binding sites simultaneously.
- Inhibited enzyme dimers from different bacterial species exhibited distinct, sequence-dependent conformations, differing from the ATP-bound state.
Conclusions:
- The determined structures reveal a novel inhibition mechanism for coumermycin A1.
- These findings support the rational design of coumermycin A1 derivatives for enhanced antibiotherapy.
- The structural insights are valuable for biotechnology applications involving DNA gyrase.
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