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PDBsum entry 2fjw
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Transferase/DNA
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PDB id
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2fjw
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References listed in PDB file
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Key reference
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Title
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A high-Throughput, High-Resolution strategy for the study of site-Selective DNA binding agents: analysis of a "highly twisted" benzimidazole-Diamidine.
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Authors
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K.D.Goodwin,
M.A.Lewis,
F.A.Tanious,
R.R.Tidwell,
W.D.Wilson,
M.M.Georgiadis,
E.C.Long.
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Ref.
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J Am Chem Soc, 2006,
128,
7846-7854.
[DOI no: ]
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PubMed id
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Abstract
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A general strategy for the rapid structural analysis of DNA binding ligands is
described as it was applied to the study of RT29, a benzimidazole-diamidine
compound containing a highly twisted diphenyl ether linkage. By combining the
existing high-throughput fluorescent intercalator displacement (HT-FID) assay
developed by Boger et al. and a high-resolution (HR) host-guest crystallographic
technique, a system was produced that was capable of determining detailed
structural information pertaining to RT29-DNA interactions within approximately
3 days. Our application of the HT/HR strategy immediately revealed that RT29 has
a preference for 4-base pair (bp), A.T-rich sites (AATT) and a similar tolerance
and affinity for three A-T-bp sites (such as ATTC) containing a G.C bp. On the
basis of these selectivities, oligonucleotides were designed and the host-guest
crystallographic method was used to generate diffraction quality crystals.
Analysis of the resulting crystal structures revealed that the diphenyl ether
moiety of RT29 undergoes conformational changes that allow it to adopt a
crescent shape that now complements the minor groove structure. The presence of
a G.C bp in the RT29 binding site of ATTC did not overly perturb its interaction
with DNA-the compound adjusted to the nucleobases that were available through
water-mediated interactions. Our analyses suggest that the HT/HR strategy may be
used to expedite the screening of novel minor groove binding compounds leading
to a direct, HR structural determination.
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