7KU4

DNA-DB818 complex: The DNA sequence 5'-CGCGAATTCGCG-3' presents a binding site for the heterocyclic small molecule (DB818).

Summary for 7KU4

• Entry DOI: 10.2210/pdb7ku4/pdb
• Descriptor: 1:(5'-D(*CP*GP*CP*GP*AP*AP*TP*TP*CP*GP*CP*G)-3'), 2-(5-{4-[AMINO(IMINO)METHYL]PHENYL}-2-THIENYL)-1H-BENZIMIDAZOLE-6- CARBOXIMIDAMIDE DIHYDROCHLORIDE, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: dna-molecule complex, dna
• Biological source: Homo sapiens
• Total number of polymer chains: 2
• Total formula weight: 7711.52

Authors

Ogbonna, E.,Fang, Z.,Wilson, W.D. (deposition date: 2020-11-24, release date: 2021-12-01, Last modification date: 2023-10-18)

Primary citation

Ogbonna, E.N.,Paul, A.,Ross Terrell, J.,Fang, Z.,Chen, C.,Poon, G.M.K.,Boykin, D.W.,Wilson, W.D.
Drug design and DNA structural research inspired by the Neidle laboratory: DNA minor groove binding and transcription factor inhibition by thiophene diamidines.
Bioorg.Med.Chem., 68:116861-116861, 2022

PubMed Abstract: The understanding of sequence-specific DNA minor groove interactions has recently made major steps forward and as a result, the goal of development of compounds that target the minor groove is an active research area. In an effort to develop biologically active minor groove agents, we are preparing and exploring the DNA interactions of diverse diamidine derivatives with a 5'-GAATTC-3' binding site using a powerful array of methods including, biosensor-SPR methods, and X-ray crystallography. The benzimidazole-thiophene module provides an excellent minor groove recognition component. A central thiophene in a benzimidazole-thiophene-phenyl aromatic system provides essentially optimum curvature for matching the shape of the minor groove. Comparison of that structure to one with the benzimidazole replaced with an indole shows that the two structures are very similar, but have some interesting and important differences in electrostatic potential maps, the DNA minor groove binding structure based on x-ray crystallographic analysis, and inhibition of the major groove binding PU.1 transcription factor complex. The binding K for both compounds is under 10 nM and both form amidine H-bonds to DNA bases. They both have bifurcated H-bonds from the benzimidazole or indole groups to bases at the center of the -AATT- binding site. Analysis of the comparative results provides an excellent understanding of how thiophene compounds recognize the minor groove and can act as transcription factor inhibitors.

PubMed: 35661929
DOI: 10.1016/j.bmc.2022.116861

Experimental method

X-RAY DIFFRACTION (1.6 Å)