Inhibition of major groove DNA binding bZIP proteins by positive patch polyamides.
Cell permeable synthetic ligands that bind to predetermined DNA sequences offer a chemical approach to gene regulation, provided inhibition of a broad range of DNA transcription factors can be achieved. DNA minor groove binding polyamides containing aminoalkyl substituents at the N-1 of a single pyrrole residue display inhibitory effects for a bZIP protein which binds exclusively in the DNA major groove. For major groove protein inhibition, specific protein-DNA contacts along the phosphate backbone were targeted with the positively charged dimethylamino substituent on the backbone of a minor groove binding polyamide hairpin. Remarkably, these polyamides bind DNA with enhanced affinity and uncompromised specificity when compared to polyamides with the aminoalkyl moiety at the C-terminus. By adding bZIP transcription factors to the class of protein-DNA complexes that can be disrupted by minor groove binding ligands, these results may increase the functional utility of polyamides as regulators of gene expression.
Bremer
R E
RE
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Wurtz
N R
NR
Szewczyk
J W
JW
Dervan
P B
PB
D050976:Basic-Leucine Zipper Transcription Factors; D004247:DNA / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D018983:DNA Footprinting; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D003850:Deoxyribonuclease I / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005656:Fungal Proteins / Q000187:drug effects / Q000378:metabolism; D051790:G-Box Binding Factors; D009690:Nucleic Acid Conformation; D009757:Nylons / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010710:Phosphates / Q000737:chemistry; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D017186:Titrimetry; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism*
D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D051790:G-Box Binding Factors; D009757:Nylons; D010710:Phosphates; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D004247:DNA; D011494:Protein Kinases; D003850:Deoxyribonuclease I