Abstract
Fluoroquinolones are gaining increasing importance in the treatment of tuberculosis. The expression of MfpA, a member of the pentapeptide repeat family of proteins from Mycobacterium tuberculosis, causes resistance to ciprofloxacin and sparfloxacin. This protein binds to DNA gyrase and inhibits its activity. Its three-dimensional structure reveals a fold, which we have named the right-handed quadrilateral beta helix, that exhibits size, shape, and electrostatic similarity to B-form DNA. This represents a form of DNA mimicry and explains both its inhibitory effect on DNA gyrase and fluoroquinolone resistance resulting from the protein's expression in vivo.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Antitubercular Agents / chemistry
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Antitubercular Agents / pharmacology*
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Bacterial Proteins / chemistry
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Bacterial Proteins / physiology*
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Ciprofloxacin / pharmacology
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Crystallography, X-Ray
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DNA Gyrase / metabolism
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DNA, Bacterial / chemistry*
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DNA, Superhelical / chemistry
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Drug Resistance, Bacterial*
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Drug Resistance, Microbial / physiology*
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Enzyme Inhibitors / chemistry
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Escherichia coli / enzymology
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Fluoroquinolones / antagonists & inhibitors
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Fluoroquinolones / chemistry
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Fluoroquinolones / pharmacology*
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Models, Molecular
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Molecular Mimicry*
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Molecular Sequence Data
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Monomeric GTP-Binding Proteins
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Mycobacterium tuberculosis / drug effects
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Mycobacterium tuberculosis / physiology*
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Protein Conformation
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Protein Folding
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Structure-Activity Relationship
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Topoisomerase II Inhibitors
Substances
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Antitubercular Agents
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Bacterial Proteins
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DNA, Bacterial
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DNA, Superhelical
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Enzyme Inhibitors
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Fluoroquinolones
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Topoisomerase II Inhibitors
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Ciprofloxacin
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MfpA protein, Mycobacterium smegmatis
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Monomeric GTP-Binding Proteins
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DNA Gyrase
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sparfloxacin
Associated data
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PDB/2BM4
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PDB/2BM5
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PDB/2BM6
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PDB/2BM7