Abstract
The molecular chaperone DnaK assists protein folding and refolding, translocation across membranes, and regulation of the heat shock response. In Escherichia coli, the protein is a target for insect-derived antimicrobial peptides, pyrrhocoricins. We present here the X-ray crystallographic analysis of the E. coli DnaK substrate-binding domain in complex with pyrrhocoricin-derived peptide inhibitors. The structures show that pyrrhocoricins act as site-specific, dual-mode (competitive and allosteric) inhibitors, occupying the substrate-binding tunnel and disrupting the latch between the lid and the beta-sandwich. Our structural analysis revealed an allosteric coupling between the movements of the lid and the interdomain linker, identifying a previously unknown mechanism of the lid-mediated regulation of the chaperone cycle.
MeSH terms
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Allosteric Site*
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Amino Acid Sequence
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Animals
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Antimicrobial Cationic Peptides / chemistry
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Antimicrobial Cationic Peptides / metabolism*
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Antimicrobial Cationic Peptides / pharmacology
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Binding Sites
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Binding, Competitive
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Crystallography, X-Ray
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Escherichia coli / metabolism*
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Escherichia coli Proteins / antagonists & inhibitors*
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Escherichia coli Proteins / chemistry*
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Escherichia coli Proteins / metabolism
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HSP70 Heat-Shock Proteins / antagonists & inhibitors*
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HSP70 Heat-Shock Proteins / chemistry*
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HSP70 Heat-Shock Proteins / metabolism
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Insect Proteins / chemistry
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Insect Proteins / metabolism*
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Insect Proteins / pharmacology
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Models, Molecular
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Molecular Chaperones / antagonists & inhibitors
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Molecular Chaperones / chemistry*
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Molecular Chaperones / metabolism
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Molecular Sequence Data
Substances
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Antimicrobial Cationic Peptides
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Escherichia coli Proteins
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HSP70 Heat-Shock Proteins
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Insect Proteins
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Molecular Chaperones
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pyrrhocoricin protein, Pyrrhocoris apterus
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dnaK protein, E coli
Associated data
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PDB/3DPO
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PDB/3DPP
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PDB/3DPQ