5e7n
From Proteopedia
Crystal Structure of RPA70N in complex with VU0085636
Structural highlights
FunctionRFA1_HUMAN Plays an essential role in several cellular processes in DNA metabolism including replication, recombination and DNA repair. Binds and subsequently stabilizes single-stranded DNA intermediates and thus prevents complementary DNA from reannealing.[1] [2] Functions as component of the alternative replication protein A complex (aRPA). aRPA binds single-stranded DNA and probably plays a role in DNA repair; it does not support chromosomal DNA replication and cell cycle progression through S-phase. In vitro, aRPA cannot promote efficient priming by DNA polymerase alpha but supports DNA polymerase delta synthesis in the presence of PCNA and replication factor C (RFC), the dual incision/excision reaction of nucleotide excision repair and RAD51-dependent strand exchange.[3] [4] Publication Abstract from PubMedReplication 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. Identification and Optimization of Anthranilic Acid Based Inhibitors of Replication Protein A.,Patrone JD, Pelz NF, Bates BS, Souza-Fagundes EM, Vangamudi B, Camper DV, Kuznetsov AG, Browning CF, Feldkamp MD, Frank AO, Gilston BA, Olejniczak ET, Rossanese OW, Waterson AG, Chazin WJ, Fesik SW ChemMedChem. 2016 Jan 8. doi: 10.1002/cmdc.201500479. PMID:26748787[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Homo sapiens | Large Structures | Bates BS | Browning CF | Camper D | Chazin WJ | Feldkamp MD | Fesik SW | Gilston BA | Kuznetsov A | Olejniczak ET | Patrone JD | Pelz NF | Rossanese OW | Souza-Fagundes EM | Vangamudi B | Waterson AG
