4nb3
From Proteopedia
Crystal structure of RPA70N in complex with a 3,4 dichlorophenylalanine ATRIP derived peptide
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 PubMedStapled helix peptides can serve as useful tools for inhibiting protein-protein interactions but can be difficult to optimize for affinity. Here we describe the discovery and optimization of a stapled helix peptide that binds to the N-terminal domain of the 70 kDa subunit of replication protein A (RPA70N). In addition to applying traditional optimization strategies, we employed a novel approach for efficiently designing peptides containing unnatural amino acids. We discovered hot spots in the target protein using a fragment-based screen, identified the amino acid that binds to the hot spot, and selected an unnatural amino acid to incorporate, based on the structure-activity relationships of small molecules that bind to this site. The resulting stapled helix peptide potently and selectively binds to RPA70N, does not disrupt ssDNA binding, and penetrates cells. This peptide may serve as a probe to explore the therapeutic potential of RPA70N inhibition in cancer. Discovery of a Potent Stapled Helix Peptide That Binds to the 70N Domain of Replication Protein A.,Frank AO, Vangamudi B, Feldkamp MD, Souza-Fagundes EM, Luzwick JW, Cortez D, Olejniczak ET, Waterson AG, Rossanese OW, Chazin WJ, Fesik SW J Med Chem. 2014 Feb 19. PMID:24491171[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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