Research in the Verdine group focuses on the structure and function of nucleic acids, with particular attention to the interactions of nucleic acids and proteins. We pursue a multi-disciplinary approach combining aspects of computational chemistry, biochemistry and molecular biology, spectroscopy, and organic synthesis. Current research projects are concentrated in three specific areas: transcription factors, catalytic DNA binding proteins, and conformationally constrained nucleic acid molecules.
In our studies on transcription factors, we are developing chemical tools with which to decipher the structural basis for sequence discrimination in protein-DNA complexes. These tools probe hydrogen-bonding and hydrophobic interactions in the contact interface, as well as dynamic factors such as DNA bendability and twistability. The proteins being studied are all involved in signal-dependent transcriptional activation. By studying the logic that nature employs to create sequence-specific DNA binding molecules, we hope eventually to apply these principles toward de novo design of transcriptional modulators.
Current studies on catalytic DNA binding proteins center on those that add methyl groups to DNA and those that repair aberrantly methylated DNA. We wish to understand how DNA behaves as a substrate, and how damaged DNA is recognized specifically and repaired. These studies may lead to a greater understanding of genomic husbandry in general and how defects in these systems contribute to cell transformation.
In the area of constrained nucleic acid molecules, we have developed chemistry that allows one to introduce disulfide cross-links into DNA and RNA molecules at predetermined positions. Disulfide cross-links are being implanted into DNA molecules in such a way as to force them to deviate from a ground-state conformation; by this strategy, we hope to gain fundamental insight into how DNA repsonds structurally to torsional stress, which should in turn shed light on deformation of DNA by proteins. Our molecular device is also being introduced into RNA molecules so as to lock them into single folding architecture. These conformationlly locked RNA structures are intended for use in structural and functional studies; for example, to define the minimal RNA element required for sequence-specific recognition by proteins, or to relate conformational mobility to catalytic activity in ribozymes.
Selected Publications:
McCaffrey, P. G.; Luo, C.; Kerppola, T. K.; Jain, J.; Badalian, T. M.; Ho, A. M.; Burgeon, E.; Lane, W. S.; Lambert, J. N.; Curran, T.; Verdine, G. L.; Rao, A.; Hogan, P. G. (1993). Isolation of the cyclosporin-sensitive T cell transcription factor NFATp. Science 262:750-754.
Müller, C. W.; Rey, F. A.; Sodeoka, M.; Verdine, G. L.; Harrison, S.C. (1995). Structure of the NF-kB p50 Homodimer Bound to DNA. Nature 373:311-317.
Schärer, O.D. and Verdine, G.L. (1995). A designed inhibitor of base-excision DNA repair. J. Am. Chem. Soc. 117:10781-10782.