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PDBsum entry 3fsi
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Transferase/DNA
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PDB id
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3fsi
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References listed in PDB file
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Key reference
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Title
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Crystal structure of a trypanocidal 4,4'-Bis(imidazolinylamino)diphenylamine bound to DNA.
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Authors
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L.S.Glass,
B.Nguyen,
K.D.Goodwin,
C.Dardonville,
W.D.Wilson,
E.C.Long,
M.M.Georgiadis.
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Ref.
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Biochemistry, 2009,
48,
5943-5952.
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PubMed id
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Abstract
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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.
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