4NB3

Crystal structure of RPA70N in complex with a 3,4 dichlorophenylalanine ATRIP derived peptide

Summary for 4NB3

• Entry DOI: 10.2210/pdb4nb3/pdb
• Descriptor: Replication protein A 70 kDa DNA-binding subunit, 3,4 dichlorophenylalanine ATRIP derived peptide (3 entities in total)
• Functional Keywords: ob fold, protein-protein interaction, 3, 4 dichlorophenylalanine, peptide binding protein
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: P27694
• Total number of polymer chains: 4
• Total formula weight: 31427.78

Authors

Feldkamp, M.D.,Frank, A.O.,Vangamudi, B.,Souza-Fagundes, E.M.,Luzwik, J.W.,Cortez, D.,Olejniczak, O.T.,Waterson, A.G.,Rossanese, O.W.,Fesik, S.W.,Chazin, W.J. (deposition date: 2013-10-22, release date: 2014-02-26, Last modification date: 2024-11-06)

Primary citation

Frank, A.O.,Vangamudi, B.,Feldkamp, M.D.,Souza-Fagundes, E.M.,Luzwick, J.W.,Cortez, D.,Olejniczak, E.T.,Waterson, A.G.,Rossanese, O.W.,Chazin, W.J.,Fesik, S.W.
Discovery of a Potent Stapled Helix Peptide That Binds to the 70N Domain of Replication Protein A.
J.Med.Chem., 57:2455-2461, 2014

PubMed Abstract: Stapled 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.

PubMed: 24491171
DOI: 10.1021/jm401730y

Experimental method

X-RAY DIFFRACTION (1.35 Å)