Structural constraints for DNA recognition by Myc and other b-HLH-ZIP proteins: design of oncoprotein analogues.
DNA recognition is a critical property of many transcription factors, some of which play important roles in human disease. Disruption of this recognition may profoundly influence the biology of these factors. One such factor, the Myc oncoprotein, utilizes a basic/helix-loop-helix/leucine zipper motif to recognize the DNA target CACGTG. As discussed here, this recognition appears to occur through recognition by one face of a basic region alpha helix utilizing amino acid side chains highly conserved among CACGTG binding proteins. This basic domain alpha helix, however, requires DNA binding for stabilization. To circumvent this energetic requirement, analogues were produced that introduce multiple alanines, displaying substantially increased spontaneous alpha helicity and significantly enhanced DNA affinity. These studies simplify our understanding of the structural constraints for DNA recognition by this family and may serve as a template for the design of small molecule transcription-targeted therapeutics.
Takemoto
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Division of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Fisher
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D000595:Amino Acid Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018257:Helix-Loop-Helix Motifs; D016350:Leucine Zippers; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D014157:Transcription Factors
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D010455:Peptides; D016271:Proto-Oncogene Proteins c-myc; D011993:Recombinant Fusion Proteins; C064972:TFEB protein, human; D014157:Transcription Factors; D004247:DNA