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| Nuclear Magnetic Resonance Investigations of the Three-Dimensional Structure and Dynamics of Proteins in Solution |
We are using multidimensional nuclear magnetic resonance (NMR) spectroscopy to investigate the structures and dynamics of proteins in solution. Such studies are essential for understanding the mechanisms of action of these proteins and for elucidating structure-function relationships
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Transcription factor - Nucleic acid Interactions
NMR methods are being used to determine the 3-dimensional structures and intramolecular dynamics of zinc finger motifs from several eukaryotic transcriptional regulatory proteins, both free and complexed with target nucleic acid. Zinc fingers are among the most abundant domains in eukaryotic genomes. They play a central role in the regulation of gene expression at both the transcriptional and the posttranscriptional level, mediated through their interactions with DNA, RNA, or protein components of the transcriptional machinery. The C2H2 zinc finger, first identified in transcription factor IIIA (TFIIIA), is used by numerous transcription factors to achieve sequence-specific recognition of DNA. Growing evidence, however, indicates that some C2H2 zinc finger proteins control gene expression both through their interactions with DNA regulatory elements and, at the posttranscriptional level, through binding to RNA. |
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Protein-Protein Interactions in Transcriptional Regulation |
Transcriptional regulation in eukaryotes relies on protein-protein interactions between DNA-bound factors and coactivators that, in turn, interact with the basal transcription machinery. The transcriptional coactivator CREB-binding protein (CBP) and its homolog p300 play an essential role in cell growth, differentiation, and development. Understanding the molecular mechanisms by which CBP and p300 recognize their various target proteins is of fundamental biomedical importance. CBP and p300 have been implicated in diseases such as leukemia, cancer, and mental retardation and are novel targets for therapeutic intervention. |
Folding of Proteins and Protein Fragments |
The molecular mechanism by which proteins fold into their 3-dimensional structures remains one of the most important unsolved problems in structural biology. Nuclear magnetic resonance (NMR) spectroscopy is uniquely suited to provide information on the structure of transient intermediates formed during protein folding. Previously, we used NMR methods to show that many peptide fragments of proteins have a tendency to adopt folded conformations in water solution. The presence of transiently populated folded structures, including reverse turns, helices, nascent helices, and hydrophobic clusters, in water solutions of short peptides has important implications for initiation of protein folding. Formation of elements of secondary structure probably plays an important role in the initiation of protein folding by reducing the number of conformations that must be explored by the polypeptide chain and by directing subsequent folding pathways. |
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