Allosteric coupling between the lid and interdomain linker in DnaK revealed by inhibitor binding studies.
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.
Liebscher
Markus
M
Martin Luther University Halle-Wittenberg, Saale, Germany.
Roujeinikova
Anna
A
D000495:Allosteric Site; D000595:Amino Acid Sequence; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D019476:Insect Proteins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data
D023181:Antimicrobial Cationic Peptides; D029968:Escherichia coli Proteins; D018840:HSP70 Heat-Shock Proteins; D019476:Insect Proteins; D018832:Molecular Chaperones; C087710:pyrrhocoricin protein, Pyrrhocoris apterus; C063842:dnaK protein, E coli