4IJH

Fragment-based Discovery of Protein-Protein Interaction Inhibitors of Replication Protein A

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.189 
  • R-Value Work: 0.149 
  • R-Value Observed: 0.151 

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Literature

Discovery of Protein-Protein Interaction Inhibitors of Replication Protein A.

Patrone, J.D., Kennedy, J.P., Frank, A.O., Feldkamp, M.D., Vangamudi, B., Pelz, N.F., Rossanese, O.W., Waterson, A.G., Chazin, W.J., Fesik, S.W.

(2013) ACS Med Chem Lett 4: 601-605

  • DOI: https://doi.org/10.1021/ml400032y
  • Primary Citation of Related Structures:  
    4IJH, 4IJL

  • PubMed Abstract: 

    Replication Protein A (RPA) is a ssDNA binding protein that is essential for DNA replication and repair. The initiation of the DNA damage response by RPA is mediated by protein-protein interactions involving the N-terminal domain of the 70 kDa subunit with partner proteins. Inhibition of these interactions increases sensitivity towards DNA damage and replication stress and may therefore be a potential strategy for cancer drug discovery. Towards this end, we have discovered two lead series of compounds, derived from hits obtained from a fragment-based screen, that bind to RPA70N with low micromolar affinity and inhibit the binding of an ATRIP-derived peptide to RPA. These compounds may offer a promising starting point for the discovery of clinically useful RPA inhibitors.

    • Organizational Affiliation: 

    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232 (USA).


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Replication protein A 70 kDa DNA-binding subunit123Homo sapiensMutation(s): 1 
Gene Names: REPA1, RPA1, RPA70
UniProt & NIH Common Fund Data Resources
Find proteins for P27694 (Homo sapiens)
Explore P27694 
Go to UniProtKB:  P27694
PHAROS:  P27694
GTEx:  ENSG00000132383 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP27694
Sequence Annotations
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
1EJ PDBBind:  4IJH Kd: 4.70e+4 (nM) from 1 assay(s)
Binding MOAD:  4IJH Kd: 4.70e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.189 
  • R-Value Work: 0.149 
  • R-Value Observed: 0.151 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 37.871α = 90
b = 52.629β = 90
c = 54.518γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
PHENIXmodel building
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-08-14
    Type: Initial release
  • Version 1.1: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description