4LUO

Fragment-Based Discovery of a Potent Inhibitor of Replication Protein A Protein-Protein Interactions

Summary for 4LUO

• Entry DOI: 10.2210/pdb4luo/pdb
• Related: 4LUV 4LUZ 4LW1 4LWC
• Descriptor: Replication protein A 70 kDa DNA-binding subunit, 1-(3-methylphenyl)-5-phenyl-1H-pyrazole-3-carboxylic acid (3 entities in total)
• Functional Keywords: ob-fold, protein-protein interaction, protein binding
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus : P27694
• Total number of polymer chains: 1
• Total formula weight: 14054.34

Authors

Feldkamp, M.D.,Frank, A.O.,Kennedy, J.P.,Waterson, A.G.,Olejniczak, E.T.,Pelz, N.F.,Patrone, J.D.,Vangamudi, B.,Camper, D.V.,Rossanese, O.W.,Fesik, S.W.,Chazin, W.J. (deposition date: 2013-07-25, release date: 2013-12-11, Last modification date: 2023-09-20)

Primary citation

Frank, A.O.,Feldkamp, M.D.,Kennedy, J.P.,Waterson, A.G.,Pelz, N.F.,Patrone, J.D.,Vangamudi, B.,Camper, D.V.,Rossanese, O.W.,Chazin, W.J.,Fesik, S.W.
Discovery of a potent inhibitor of replication protein a protein-protein interactions using a fragment-linking approach.
J.Med.Chem., 56:9242-9250, 2013

PubMed Abstract: Replication protein A (RPA), the major eukaryotic single-stranded DNA (ssDNA)-binding protein, is involved in nearly all cellular DNA transactions. The RPA N-terminal domain (RPA70N) is a recruitment site for proteins involved in DNA-damage response and repair. Selective inhibition of these protein-protein interactions has the potential to inhibit the DNA-damage response and to sensitize cancer cells to DNA-damaging agents without affecting other functions of RPA. To discover a potent, selective inhibitor of the RPA70N protein-protein interactions to test this hypothesis, we used NMR spectroscopy to identify fragment hits that bind to two adjacent sites in the basic cleft of RPA70N. High-resolution X-ray crystal structures of RPA70N-ligand complexes revealed how these fragments bind to RPA and guided the design of linked compounds that simultaneously occupy both sites. We have synthesized linked molecules that bind to RPA70N with submicromolar affinity and minimal disruption of RPA's interaction with ssDNA.

PubMed: 24147804
DOI: 10.1021/jm401333u

Experimental method

X-RAY DIFFRACTION (1.54 Å)