title: Allosteric inhibition of zinc-finger binding in the major groove of DNA by minor-groove binding ligands.
abstract: In recent years, two methods have been developed that may eventually allow the targeted regulation of a broad repertoire of genes. The engineered protein strategy involves selecting Cys(2)His(2) zinc finger proteins that will recognize specific sites in the major groove of DNA. The small molecule approach utilizes pairing rules for pyrrole-imidazole polyamides that target specific sites in the minor groove. To understand how these two methods might complement each other, we have begun exploring how polyamides and zinc fingers interact when they bind the same site on opposite grooves of DNA. Although structural comparisons show no obvious source of van der Waals collisions, we have found a significant "negative cooperativity" when the two classes of compounds are directed to the overlapping sites. Examining available crystal structures suggests that this may reflect differences in the precise DNA conformation, especially with regard to width and depth of the grooves, that is preferred for binding. These results may give new insights into the structural requirements for zinc finger and polyamide binding and may eventually lead to the development of even more powerful and flexible schemes for regulating gene expression.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
authors.forename: Doan H
authors.initials: DH
authors.lastname: Nguyen-Hackley
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ramm
authors.forename: Christina M
authors.initials: CM
authors.lastname: Taylor
authors.forename: J Keith
authors.initials: JK
authors.lastname: Joung
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dervan
authors.forename: Carl O
authors.initials: CO
authors.lastname: Pabo
mesh_terms: D000494:Allosteric Regulation; D001483:Base Sequence; D001667:Binding, Competitive; D003198:Computer Simulation; D004247:DNA / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D018983:DNA Footprinting; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D003850:Deoxyribonuclease I / Q000737:chemistry; D051766:Early Growth Response Protein 1; D024202:Electrophoretic Mobility Shift Assay; D005656:Fungal Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009757:Nylons / Q000737:chemistry; D011485:Protein Binding; D035181:TATA-Box Binding Protein / Q000037:antagonists & inhibitors / Q000737:chemistry; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000737:chemistry; D016335:Zinc Fingers
chemical_list: C094153:AREA protein, Penicillium chrysogenum; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D005656:Fungal Proteins; D017874:Immediate-Early Proteins; D008024:Ligands; D009757:Nylons; D035181:TATA-Box Binding Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D004247:DNA; D003850:Deoxyribonuclease I