7AZG

DNA polymerase sliding clamp from Escherichia coli with peptide 4 bound

Summary for 7AZG

• Entry DOI: 10.2210/pdb7azg/pdb
• Descriptor: Beta sliding clamp, Peptide 4 (3 entities in total)
• Functional Keywords: antibacterial drug, dna binding protein
• Biological source: Escherichia coli 2-427-07_S4_C3; More
• Total number of polymer chains: 16
• Total formula weight: 348381.81

Authors

Monsarrat, C.,Compain, G.,Andre, C.,Martiel, I.,Engilberge, S.,Olieric, V.,Wolff, P.,Brillet, K.,Landolfo, M.,Silva da Veiga, C.,Wagner, J.,Guichard, G.,Burnouf, D.Y. (deposition date: 2020-11-16, release date: 2021-12-01, Last modification date: 2024-01-31)

Primary citation

Monsarrat, C.,Compain, G.,Andre, C.,Engilberge, S.,Martiel, I.,Olieric, V.,Wolff, P.,Brillet, K.,Landolfo, M.,Silva da Veiga, C.,Wagner, J.,Guichard, G.,Burnouf, D.Y.
Iterative Structure-Based Optimization of Short Peptides Targeting the Bacterial Sliding Clamp.
J.Med.Chem., 64:17063-17078, 2021

PubMed Abstract: The bacterial DNA sliding clamp (SC), or replication processivity factor, is a promising target for the development of novel antibiotics. We report a structure-activity relationship study of a new series of peptides interacting within the SC (SC) binding pocket. Various modifications were explored including N-alkylation of the peptide bonds, extension of the N-terminal moiety, and introduction of hydrophobic and constrained residues at the C-terminus. In each category, single modifications were identified that increased affinity to SC. A combination of such modifications yielded in several cases to a substantially increased affinity compared to the parent peptides with in the range of 30-80 nM. X-ray structure analysis of 11 peptide/SC co-crystals revealed new interactions at the peptide-protein interface (i.e., stacking interactions, hydrogen bonds, and hydrophobic contacts) that can account for the improved binding. Several compounds among the best binders were also found to be more effective in inhibiting SC-dependent DNA synthesis.

PubMed: 34806883
DOI: 10.1021/acs.jmedchem.1c00918

Experimental method

X-RAY DIFFRACTION (2.92 Å)