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

LaTeca S. Glass, Binh Nguyen, Kristie D. Goodwin, Christophe Dardonville, W. David Wilson, Eric C. Long, Millie Georgiadis

Research output: Contribution to journalArticle

28 Citations (Scopus)

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 Å 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.

Original languageEnglish
Pages (from-to)5943-5952
Number of pages10
JournalBiochemistry
Volume48
Issue number25
DOIs
StatePublished - Jun 30 2009

Fingerprint

Diphenylamine
Crystal structure
DNA
Oligonucleotides
Electron energy levels
Hydrogen
Hydrogen bonds
Binding Sites
Ligands
Molecules

ASJC Scopus subject areas

  • Biochemistry

Cite this

Glass, L. S., Nguyen, B., Goodwin, K. D., Dardonville, C., Wilson, W. D., Long, E. C., & Georgiadis, M. (2009). Crystal structure of a trypanocidal 4,4′-bis(imidazolinylamino) diphenylamine bound to DNA. Biochemistry, 48(25), 5943-5952. https://doi.org/10.1021/bi900204w

Crystal structure of a trypanocidal 4,4′-bis(imidazolinylamino) diphenylamine bound to DNA. / Glass, LaTeca S.; Nguyen, Binh; Goodwin, Kristie D.; Dardonville, Christophe; Wilson, W. David; Long, Eric C.; Georgiadis, Millie.

In: Biochemistry, Vol. 48, No. 25, 30.06.2009, p. 5943-5952.

Research output: Contribution to journalArticle

Glass, LS, Nguyen, B, Goodwin, KD, Dardonville, C, Wilson, WD, Long, EC & Georgiadis, M 2009, 'Crystal structure of a trypanocidal 4,4′-bis(imidazolinylamino) diphenylamine bound to DNA', Biochemistry, vol. 48, no. 25, pp. 5943-5952. https://doi.org/10.1021/bi900204w
Glass LS, Nguyen B, Goodwin KD, Dardonville C, Wilson WD, Long EC et al. Crystal structure of a trypanocidal 4,4′-bis(imidazolinylamino) diphenylamine bound to DNA. Biochemistry. 2009 Jun 30;48(25):5943-5952. https://doi.org/10.1021/bi900204w
Glass, LaTeca S. ; Nguyen, Binh ; Goodwin, Kristie D. ; Dardonville, Christophe ; Wilson, W. David ; Long, Eric C. ; Georgiadis, Millie. / Crystal structure of a trypanocidal 4,4′-bis(imidazolinylamino) diphenylamine bound to DNA. In: Biochemistry. 2009 ; Vol. 48, No. 25. pp. 5943-5952.
@article{f389c044b5e64e4d9086dc73b3c14c81,
title = "Crystal structure of a trypanocidal 4,4′-bis(imidazolinylamino) diphenylamine bound to DNA",
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 {\AA} 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.",
author = "Glass, {LaTeca S.} and Binh Nguyen and Goodwin, {Kristie D.} and Christophe Dardonville and Wilson, {W. David} and Long, {Eric C.} and Millie Georgiadis",
year = "2009",
month = "6",
day = "30",
doi = "10.1021/bi900204w",
language = "English",
volume = "48",
pages = "5943--5952",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "25",

}

TY - JOUR

T1 - Crystal structure of a trypanocidal 4,4′-bis(imidazolinylamino) diphenylamine bound to DNA

AU - Glass, LaTeca S.

AU - Nguyen, Binh

AU - Goodwin, Kristie D.

AU - Dardonville, Christophe

AU - Wilson, W. David

AU - Long, Eric C.

AU - Georgiadis, Millie

PY - 2009/6/30

Y1 - 2009/6/30

N2 - 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 Å 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.

AB - 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 Å 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.

UR - http://www.scopus.com/inward/record.url?scp=67649607258&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67649607258&partnerID=8YFLogxK

U2 - 10.1021/bi900204w

DO - 10.1021/bi900204w

M3 - Article

C2 - 19405506

AN - SCOPUS:67649607258

VL - 48

SP - 5943

EP - 5952

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 25

ER -