3FSI

Crystal structure of a trypanocidal 4,4'-Bis(imidazolinylamino)diphenylamine bound to DNA


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.254 
  • R-Value Work: 0.231 

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Literature

Crystal structure of a trypanocidal 4,4'-bis(imidazolinylamino)diphenylamine bound to DNA.

Glass, L.S.Nguyen, B.Goodwin, K.D.Dardonville, C.Wilson, W.D.Long, E.C.Georgiadis, M.M.

(2009) Biochemistry 48: 5943-5952

  • DOI: https://doi.org/10.1021/bi900204w
  • Primary Citation of Related Structures:  
    3FSI

  • PubMed Abstract: 

    The pursuit of small molecules that bind to DNA has led to the discovery of selective and potent antitrypanosomal agents, specifically 4,4'-bis(imidazolinylamino)- and 4,4'-bis(guanidino)diphenylamine compounds, CD27 and CD25, respectively. Although the antitrypanosomal properties of these compounds have been characterized, further development of this series of compounds requires assessment of their DNA site selectivities and affinities. Toward this end, both compounds have been analyzed and found to selectively bind AT sequences. However, CD27 was found to bind with higher affinity to 5'-AATT than 5'-ATAT while CD25 bound more weakly but equally well to either sequence. To detail the nature of its interactions with DNA, the crystal structure of CD27, bound to its preferred DNA-binding site 5'-AATT within a self-complementary oligonucleotide, 5'-d(CTTAATTCGAATTAAG), was determined at 1.75 A using a host-guest approach. Although CD27 is predicted to be highly twisted in its energy-minimized state, it adopts a more planar crescent shape when bound in the minor groove of the DNA. Interactions of CD27 with 5'-AATT include bifurcated hydrogen bonds, providing a basis for selectivity of this site, and favorable van der Waals interactions in a slightly widened minor groove. Thus, an induced fit results from conformational changes in both the ligand and the DNA. Our studies suggest a basis for understanding the mechanism of the antitrypanosomal activity of these symmetric diphenylamine compounds.


  • Organizational Affiliation

    Department of Chemistry and Chemical Biology, Purdue School of Science, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.


Macromolecules

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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Reverse transcriptase domain255Moloney murine leukemia virusMutation(s): 0 
Gene Names: MoMLVpol
EC: 2.7.7.49
UniProt
Find proteins for P03355 (Moloney murine leukemia virus (isolate Shinnick))
Explore P03355 
Go to UniProtKB:  P03355
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP03355
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains LengthOrganismImage
5'-D(*CP*TP*TP*AP*AP*TP*TP*C)-3'B [auth G]8N/A
Sequence Annotations
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  • Reference Sequence

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Entity ID: 3
MoleculeChains LengthOrganismImage
5'-D(P*GP*AP*AP*TP*TP*AP*AP*G)-3'C [auth B]8N/A
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.254 
  • R-Value Work: 0.231 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 53.743α = 90
b = 145.592β = 90
c = 46.57γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection
PHASERphasing

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-05-19
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-11-01
    Changes: Refinement description
  • Version 1.3: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description