Abstract
NAD(+)-dependent DNA ligases (LigA) are ubiquitous in bacteria and essential for growth. Their distinctive substrate specificity and domain organization vis-a-vis human ATP-dependent ligases make them outstanding targets for anti-infective drug discovery. We report here the 2.3 A crystal structure of Escherichia coli LigA bound to an adenylylated nick, which captures LigA in a state poised for strand closure and reveals the basis for nick recognition. LigA envelopes the DNA within a protein clamp. Large protein domain movements and remodeling of the active site orchestrate progression through the three chemical steps of the ligation reaction. The structure inspires a strategy for inhibitor design.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
MeSH terms
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Adenine Nucleotides / chemistry
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Base Sequence
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Catalytic Domain
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Crystallography, X-Ray
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DNA Breaks, Single-Stranded
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DNA Ligase ATP
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DNA Ligases / chemistry*
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DNA Ligases / genetics
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DNA Ligases / metabolism*
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DNA Repair
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DNA, Bacterial / chemistry
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DNA, Bacterial / genetics
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DNA, Bacterial / metabolism
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Escherichia coli / genetics
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Escherichia coli / metabolism*
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Escherichia coli Proteins / chemistry*
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Escherichia coli Proteins / genetics
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Escherichia coli Proteins / metabolism*
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Humans
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Models, Molecular
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Nucleic Acid Conformation
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Protein Conformation
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Protein Structure, Tertiary
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Species Specificity
Substances
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Adenine Nucleotides
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DNA, Bacterial
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Escherichia coli Proteins
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DNA Ligases
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DNA Ligase ATP
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LigA protein, E coli