Small molecule DnaK Modulators targeting the beta domain.
The misregulation of protein folding often results in a variety of deleterious consequences on cellular function that range from the accumulation of protein aggregates leading to neurological disorders, to the inhibition of apoptosis in cancer cells. Several essential components of the protein folding machinery have been identified. For example, molecular chaperones interact with misfolded more ..
Data Source: Sanford-Burnham Center for Chemical Genomics (SBCCG)
Source Affiliation: Sanford-Burnham Medical Research Institute (SBMRI, San Diego, CA)
Network: NIH Molecular Libraries Screening Centers Network (MLSCN)
Grant Proposal Number: XO1 MH078942
Assay Provider: Dr. Maurizio Pellecchia, Sanford-Burnham Medical Research Institute, San Diego, CA
The misregulation of protein folding often results in a variety of deleterious consequences on cellular function that range from the accumulation of protein aggregates leading to neurological disorders, to the inhibition of apoptosis in cancer cells. Several essential components of the protein folding machinery have been identified. For example, molecular chaperones interact with misfolded proteins and facilitate their refolding into native states. In E. coli, the chaperone DnaK is part of a multi-subunit complex that efficiently refolds proteins. Small molecules that inhibit DnaK could lead to a better understanding of the mechanism of chaperones and their importance in other diseases. Inhibitors of DnaK might eventually be developed into novel antibiotics.
DnaK consists of three domains: a 44 kDa nucleotide binding domain (residues 1−392), a 13kDa substrate binding domain (residues 393-507) and a 10 kDa alpha helical domain (residues 508-638). It has been proved that the substrate binding domain play a central role in the functions of chaperones. In addition, a deep hydrophobic pock of the substrate binding domain makes it a good target for the small organic molecules.
In an earlier assay we screened libraries of small molecules for their ability to interact with the substrate binding domain of DnaK(AID 1033). In this series of assays the most promising hit and its analogs were tested.
This AID summarizes the biological properties of the probe molecule, SID- 56427267(ML076), characterized by a battery of secondary assays performed in the laboratory of Dr. Maurizio Pellecchia.
The compound was found to be a poor inhibitor of ATPase(IC50 > 20 mM, AID 1494) and binds to the SBD with a Kd of 0.2 uM(AID 1495).
1. Bukau B, Weissman J, Horwich A.
Cell. 2006 May 5;125(3):443-51.
2. Pellecchia M, Montgomery DL, Stevens SY, Vander Kooi CW, Feng HP, Gierasch LM, Zuiderweg ER. Nat Struct Biol. 2000 Apr;7(4):298-303.
Probe molecules are defined as the positives of this assay and assigned a score of 100.
Categorized Comment - additional comments and annotations
From MLP Probe Report:
Probe count: 1
MLP Probe ML# for probe 1: ML076
PubChem Substance ID (SID) for probe 1: 56427267
PubChem Compound ID (CID) for probe 1: 25105719
Probe type for probe 1: Inhibitor
IC50/EC50 (nM) for probe 1: <200,000
Target for probe 1: DnaK (gi: 216546)
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK47353/ (ID: 2359550)
Grant number for probe 1: MH078942-01
PubMed Publication ID (PMID) for probe 1: 19694756
NCBI Book chapter title for probe 1: Inhibitors of Protein Folding: DnaK
Data Table (Concise)