title: Cyclic lipopeptide antibiotics bind to the N-terminal domain of the prokaryotic Hsp90 to inhibit the chaperone activity.
abstract: Chemical arrays were employed to screen ligands for HtpG, the prokaryotic homologue of Hsp (heat-shock protein) 90. We found that colistins and the closely related polymyxin B interact physically with HtpG. They bind to the N-terminal domain of HtpG specifically without affecting its ATPase activity. The interaction caused inhibition of chaperone function of HtpG that suppresses thermal aggregation of substrate proteins. Further studies were performed with one of these cyclic lipopeptide antibiotics, colistin sulfate salt. It inhibited the chaperone function of the N-terminal domain of HtpG. However, it inhibited neither the chaperone function of the middle domain of HtpG nor that of other molecular chaperones such as DnaK, the prokaryotic homologue of Hsp70, and small Hsp. The addition of colistin sulfate salt increased surface hydrophobicity of the N-terminal domain of HtpG and induced oligomerization of HtpG and its N-terminal domain. These structural changes are discussed in relation to the inhibition of the chaperone function.
authors.affiliation: Molecular Biology Course, Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Minagawa
authors.forename: Yasumitsu
authors.initials: Y
authors.lastname: Kondoh
authors.forename: Keigo
authors.initials: K
authors.lastname: Sueoka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakamoto
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003091:Colistin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057166:High-Throughput Screening Assays; D006358:Hot Temperature / Q000009:adverse effects; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D045342:Light-Harvesting Protein Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055666:Lipopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D050296:Microbial Viability / Q000187:drug effects; D009154:Mutation; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011112:Polymyxin B / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017510:Protein Folding / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D013499:Surface Properties; D046940:Synechococcus / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D018841:HSP90 Heat-Shock Proteins; D008024:Ligands; D045342:Light-Harvesting Protein Complexes; D055666:Lipopeptides; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D011994:Recombinant Proteins; C082501:cpcD phycobilisome linker protein, cyanobacteria; C066720:HtpG protein, bacteria; D000251:Adenosine Triphosphatases; D011112:Polymyxin B; D003091:Colistin