5E7N

Crystal Structure of RPA70N in complex with VU0085636

Summary for 5E7N

• Entry DOI: 10.2210/pdb5e7n/pdb
• Descriptor: Replication protein A 70 kDa DNA-binding subunit, 2-({3-[(4-bromophenyl)sulfamoyl]-4-methylbenzoyl}amino)benzoic acid (3 entities in total)
• Functional Keywords: inhibitor, complex, protein binding-inhibitor complex, protein binding/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 13987.07

Authors

Gilston, B.A.,Patrone, J.D.,Pelz, N.F.,Bates, B.S.,Souza-Fagundes, E.M.,Vangamudi, B.,Camper, D.,Kuznetsov, A.,Browning, C.F.,Feldkamp, M.D.,Olejniczak, E.T.,Rossanese, O.W.,Waterson, A.G.,Fesik, S.W.,Chazin, W.J. (deposition date: 2015-10-12, release date: 2016-01-27, Last modification date: 2023-09-27)

Primary citation

Patrone, J.D.,Pelz, N.F.,Bates, B.S.,Souza-Fagundes, E.M.,Vangamudi, B.,Camper, D.V.,Kuznetsov, A.G.,Browning, C.F.,Feldkamp, M.D.,Frank, A.O.,Gilston, B.A.,Olejniczak, E.T.,Rossanese, O.W.,Waterson, A.G.,Chazin, W.J.,Fesik, S.W.
Identification and Optimization of Anthranilic Acid Based Inhibitors of Replication Protein A.
Chemmedchem, 11:893-899, 2016

PubMed Abstract: Replication protein A (RPA) is an essential single-stranded DNA (ssDNA)-binding protein that initiates the DNA damage response pathway through protein-protein interactions (PPIs) mediated by its 70N domain. The identification and use of chemical probes that can specifically disrupt these interactions is important for validating RPA as a cancer target. A high-throughput screen (HTS) to identify new chemical entities was conducted, and 90 hit compounds were identified. From these initial hits, an anthranilic acid based series was optimized by using a structure-guided iterative medicinal chemistry approach to yield a cell-penetrant compound that binds to RPA70N with an affinity of 812 nm. This compound, 2-(3- (N-(3,4-dichlorophenyl)sulfamoyl)-4-methylbenzamido)benzoic acid (20 c), is capable of inhibiting PPIs mediated by this domain.

PubMed: 26748787
DOI: 10.1002/cmdc.201500479

Experimental method

X-RAY DIFFRACTION (1.21 Å)