4R4C

Structure of RPA70N in complex with 5-(4-((4-(5-carboxyfuran-2-yl)-2-chlorobenzamido)methyl)phenyl)-1-(3,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.189 
  • R-Value Work: 0.148 
  • R-Value Observed: 0.150 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Diphenylpyrazoles as replication protein a inhibitors.

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

(2015) ACS Med Chem Lett 6: 140-145

  • DOI: https://doi.org/10.1021/ml5003629
  • Primary Citation of Related Structures:  
    4R4C, 4R4I, 4R4O, 4R4Q, 4R4T

  • PubMed Abstract: 

    Replication Protein A is the primary eukaryotic ssDNA binding protein that has a central role in initiating the cellular response to DNA damage. RPA recruits multiple proteins to sites of DNA damage via the N-terminal domain of the 70 kDa subunit (RPA70N). Here we describe the optimization of a diphenylpyrazole carboxylic acid series of inhibitors of these RPA-protein interactions. We evaluated substituents on the aromatic rings as well as the type and geometry of the linkers used to combine fragments, ultimately leading to submicromolar inhibitors of RPA70N protein-protein interactions.


  • Organizational Affiliation

    Department of Biochemistry, Department of Pharmacology, Vanderbilt University School of Medicine, and Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States.


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: RPA1REPA1RPA70
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
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3HS
Query on 3HS

Download Ideal Coordinates CCD File 
B [auth A]5-[4-({[4-(5-carboxyfuran-2-yl)-2-chlorobenzoyl]amino}methyl)phenyl]-1-(3,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid
C29 H18 Cl3 N3 O6
KMDVWGXHTUXJOW-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3HS BindingDB:  4R4C Kd: 2900 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.189 
  • R-Value Work: 0.148 
  • R-Value Observed: 0.150 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 38.07α = 90
b = 53.864β = 90
c = 53.977γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
PHENIXmodel building
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2014-11-19
    Type: Initial release
  • Version 1.1: 2015-03-11
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description