13JG

E. coli DnaK bound to peptide PA1, structure B

This is a non-PDB format compatible entry.

Summary for 13JG

• Entry DOI: 10.2210/pdb13jg/pdb
• Related: 13IQ 13IU 13IV
• Related PRD ID: PRD_002606
• Descriptor: Chaperone protein DnaK, peptide PA1-A, SULFATE ION, ... (4 entities in total)
• Functional Keywords: allosteric inhibition, dnak, molecular chaperones, peptidomimetics, proteotoxic stress, chaperone
• Biological source: Escherichia coli
• Total number of polymer chains: 1
• Total formula weight: 24854.87

Authors

Ariza-Mateos, A.,Serganov, A. (deposition date: 2026-05-09, release date: 2026-05-27)

Primary citation

Richards, A.,Ariza-Mateos, A.,Ghosh, A.,Kim, M.,Sandler, S.,Yardumian, I.,Yawson, G.,Baryza, J.,Serganov, A.,Lupoli, T.J.
Reengineering Protease Inhibitors to Disrupt Hsp70 Chaperone Function.
Angew.Chem.Int.Ed.Engl., :e1777033-e1777033, 2026

PubMed Abstract: The heat shock protein 70 (Hsp70) family consists of ATP-driven molecular chaperones essential for maintaining protein homeostasis (proteostasis) across all cell types, however, modulation of chaperone activity by small molecules remains challenging. In bacteria, a major Hsp70 called DnaK represents a putative antibacterial target, as it plays essential roles in growth, antibiotic resistance, and stress response. While Hsp70 inhibitors are in development as potential cancer and neurodegenerative disease treatments in humans, we lack generalizable methods to target Hsp70s across species. Here, we address how peptidomimetic scaffolds designed to inhibit proteases, exemplified by the drug telaprevir, interact with two different bacterial DnaKs to disrupt chaperone function. We perform extensive structure-function studies of telaprevir analogs against DnaK to inform the design of synthetic unnatural peptide sequences with a range of inhibitory potencies. X-ray crystallography analysis of telaprevir and several synthetic peptidomimetics reveal interactions with DnaK's substrate binding domain via ligand side chain recognition reminiscent of that observed in protease active sites, but in two orientations. These co-complexes inspire the synthesis of shorter peptidomimetics capable of allosterically inhibiting DnaK's ATPase activity. Overall, this work demonstrates that chemical scaffolds devised for protease inhibition may be modified to disrupt Hsp70 chaperone activities.

PubMed: 42154608
DOI: 10.1002/anie.1777033

Experimental method

X-RAY DIFFRACTION (1.52 Å)