13iv

E. coli DaK bound to peptide PA1, structure A

spinqualitylabelsall models 13iv, resolution 3.23Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 13iv is a 2 chain structure with sequence from Escherichia coli. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.23Å Ligands: A1DFX Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DNAK_ECO57 Acts as a chaperone. Publication Abstract from PubMed 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. Reengineering Protease Inhibitors to Disrupt Hsp70 Chaperone Function.,Richards A, Ariza-Mateos A, Ghosh A, Kim M, Sandler S, Yardumian I, Yawson G, Baryza J, Serganov A, Lupoli TJ Angew Chem Int Ed Engl. 2026 May 19:e1777033. doi: 10.1002/anie.1777033. PMID:42154608 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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