4IJL

Fragment-based Discovery of Protein-Protein Interaction Inhibitors of Replication Protein A

Summary for 4IJL

• Entry DOI: 10.2210/pdb4ijl/pdb
• Related: 4IJH
• Descriptor: Replication protein A 70 kDa DNA-binding subunit, {[5-(3-chloro-1-benzothiophen-2-yl)-4-phenyl-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid (3 entities in total)
• Functional Keywords: ob-fold, protein-protein interaction, dna binding protein-inhibitor complex, dna binding protein/inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P27694
• Total number of polymer chains: 1
• Total formula weight: 14301.51

Authors

Feldkamp, M.D.,Patrone, J.D.,Kennedy, J.P.,Frank, A.O.,Vangamudi, B.,Pelz, N.F.,Rossanese, O.W.,Waterson, A.G.,Fesik, S.W.,Chazin, W.J. (deposition date: 2012-12-21, release date: 2013-08-14, Last modification date: 2023-09-20)

Primary citation

Patrone, J.D.,Kennedy, J.P.,Frank, A.O.,Feldkamp, M.D.,Vangamudi, B.,Pelz, N.F.,Rossanese, O.W.,Waterson, A.G.,Chazin, W.J.,Fesik, S.W.
Discovery of Protein-Protein Interaction Inhibitors of Replication Protein A.
ACS MED.CHEM.LETT., 4:601-605, 2013

PubMed Abstract: Replication Protein A (RPA) is a ssDNA binding protein that is essential for DNA replication and repair. The initiation of the DNA damage response by RPA is mediated by protein-protein interactions involving the N-terminal domain of the 70 kDa subunit with partner proteins. Inhibition of these interactions increases sensitivity towards DNA damage and replication stress and may therefore be a potential strategy for cancer drug discovery. Towards this end, we have discovered two lead series of compounds, derived from hits obtained from a fragment-based screen, that bind to RPA70N with low micromolar affinity and inhibit the binding of an ATRIP-derived peptide to RPA. These compounds may offer a promising starting point for the discovery of clinically useful RPA inhibitors.

PubMed: 23914285
DOI: 10.1021/ml400032y

Experimental method

X-RAY DIFFRACTION (1.7 Å)