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DNA in eukaryotic cells is packaged by histone proteins into chromatin, a dynamic hierarchical organization underlying genomic function. The basic chromatin building block is the nucleosome core particle, in which ~147 base pairs of DNA are wrapped in 1 & 2/3 superhelical turns around a histone protein octamer. Our high resolution crystallographic analysis of the nucleosome core particle yielded a wealth of insight into histone-DNA association. In fact, the conformation of DNA in the nucleosome core is remarkably different than its naked form or that associated with other nuclear proteins and is dependent on both DNA sequence and positioning on the histone octamer. We found that even divalent metal hydrates can recognize this unique feature of the nucleosome, binding in a DNA sequence- and orientation-selective manner.
Our present goal is to find new drug targets and develop novel therapeutics by studying DNA structure and chemistry within a physiological framework. Approximately 83% of genomic DNA is associated with histone octamers, rendering the nucleosome core an important therapeutic target. However, relatively little is known about the influence of histone packaging on DNA-drug interaction. Since nucleosomal DNA displays sequence- and context-dependent structural features that can be recognized by even simple small molecules, the main premise of our present investigations is to explore the possibilities for nucleosome-selective recognition by medicinal agents and nuclear protein factors. The discovery of nucleosome-specific compounds would hold promise for the acquisition of improved therapeutic agents by allowing for a level of site discrimination beyond the primary structure of DNA.
DNA in eukaryotic cells is packaged by histone proteins into chromatin, a dynamic hierarchical organization underlying genomic function. The basic chromatin building block is the nucleosome core particle, in which ~147 base pairs of DNA are wrapped in 1 & 2/3 superhelical turns around a histone protein octamer. Our high resolution crystallographic analysis of the nucleosome core particle yielded a wealth of insight into histone-DNA association. In fact, the conformation of DNA in the nucleosome core is remarkably different than its naked form or that associated with other nuclear proteins and is dependent on both DNA sequence and positioning on the histone octamer. We found that even divalent metal hydrates can recognize this unique feature of the nucleosome, binding in a DNA sequence- and orientation-selective manner.
Our present goal is to find new drug targets and develop novel therapeutics by studying DNA structure and chemistry within a physiological framework. Approximately 83% of genomic DNA is associated with histone octamers, rendering the nucleosome core an important therapeutic target. However, relatively little is known about the influence of histone packaging on DNA-drug interaction. Since nucleosomal DNA displays sequence- and context-dependent structural features that can be recognized by even simple small molecules, the main premise of our present investigations is to explore the possibilities for nucleosome-selective recognition by medicinal agents and nuclear protein factors. The discovery of nucleosome-specific compounds would hold promise for the acquisition of improved therapeutic agents by allowing for a level of site discrimination beyond the primary structure of DNA.
Research Interests
Papers共 105 篇Author StatisticsCo-AuthorSimilar Experts
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#Papers: 103
#Citation: 7059
H-Index: 27
G-Index: 45
Sociability: 5
Diversity: 2
Activity: 31
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