4NB3: Crystal Structure Of Rpa70n In Complex With A 3,4 Dichlorophenylalanine Atrip Derived Peptide

Citation:
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.
PDB ID: 4NB3Download
MMDB ID: 117859
PDB Deposition Date: 2013/10/22
Updated in MMDB: 2014/04
Experimental Method:
x-ray diffraction
Resolution: 1.35  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 4NB3: dimeric; determined by author
Molecular Components in 4NB3
Label Count Molecule
Proteins (2 molecules)
1
Replication Protein a 70 KDA DNA-binding Subunit(Gene symbol: RPA1)
Molecule annotation
1
3,4 Dichlorophenylalanine Atrip Derived Peptide
Molecule annotation
* Click molecule labels to explore molecular sequence information.

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