P. Shing Ho
Contact Information:
Shing.Ho@ColoState.edu
Office Number: MRB 340
Phone Number: 970-491-5566
Fax Number: 970-491-0494
Research Title:
Nucleic acid structure and function, X-ray crystallography
Research Description:
The research interests in our laboratory have been focused on the structures and structural gymnastics of nucleic acids and their function, and, more recently, on controlling macromolecular structure and stability through halogen bonds for biomolecular engineering applications. To attack these problems, we apply X-ray crystallography, computational biology, biochemistry, and bioinformatics approaches.
The exchange of genetic material during recombination, DNA repair, or integration of foreign DNAs involves formation of a four-stranded structure (the Holliday junction) in which one strand of a double-helix exchanging with another duplex by forming a four-stranded Holliday junction. We are currently studying the structural determinants for the formation and stabilization of Holliday junctions in crystals and in solution. Using a unique crystal system that accommodates both B-DNA and A-DNA duplexes and the four-stranded intermediate, we have been able to construct a unique phase map that walks through sequence-conformation space in single-nucleotide steps. This has allowed us to develop models for the role that sequence-dependent formation of the Holliday junction plays in recombination events.
In 1979, a left-handed alternative to Watson and Crick's right-handed double-helical B-DNA model was discovered. This structure (called Z-DNA) has now been implicated in a number of different eukaryotic processes, including RNA editing, coactivation of transcription, and large scale-genomic deletions. We have been mapping the occurrence of Z-DNA across genomes of organisms ranging from eubacteria to archae-bacteria to lower and higher eukaryotes. This phylogenomic analysis has provided us with a map of how and where GC-rich transcriptional elements, including Z-DNA has emerged, and suggest a mechanism for the migration of such elements towards the sites transcriptional initiation through functional evolution. We are now applying this strategy to develop phylogenetic maps to relate organisms based on global functional rather than simple sequence information.
We have recently "rediscovered" a class of molecular interactions (termed "halogen bonds" by chemists), which are analogous to the better known hydrogen bond. This interaction is unusual in that molecular halogens (chlorine, bromine, and iodine) serve as the electropositive Lewis acid that form stabilizing interactions with oxygens, nitrogens, sulfurs, and even the negatively charged phosphate oxygens of nucleic acids. Such interactions were found to be prevalent in protein-ligand interactions, and to affect the conformation of DNAs and RNAs. Using the Holliday junction as a model, we have demonstrated that a halogen bond can be engineered to specifically direct the conformation of a macromolecule, and is 2-5 kcal/mol more stable than a comparable hydrogen bond in this environment. We are now applying this interaction as a general tool to engineer protein stability, intermolecular interactions, and for the design of new and more effective inhibitors and drugs.
Selected Publications:
Brandt F. Eichman, Jeffery M. Varagason, Blaine H.M. Mooers, and P. Shing Ho (2000) "The Holliday junction in an inverted repeat DNA sequence: Sequence effects on the structure of four-way junctions", Proc. Natl. Acad. Sci., USA, 97, 3971-3976.
Jeffrey M. Vargason, Brandt F. Eichman, and P. Shing Ho (2000) "The extended and eccentric E-DNA structure induced by cytosine methylation or bromination", Nature Struct. Biol., 7, 758-761.
Eichman, B. F., Mooers, B. H. M., Alberti, M., Hearst, J.E., and Ho, P. S. (2001) "The crystal structures of psoralen cross-linked DNAs: Drug dependent formation of Holliday junctions", J. Mol. Biol., 308, 15-26 (cover article).
Vargasen, J. M., Henderson, K. and Ho, P. S. (2001) "Crystallographic map of the B-DNA to A-DNA transition", Proc. Natl. Acad. Sci., USA, 98, 7265-7270.
Auffinger, P., Hays, F. A., Westhof, E., and Ho, P.S. (2004) "Halogen bonds in biological molecules", Proc. Natl. Acad. Sci., USA. 101, 16789-16794.
Hays, F. A., Teegarden, A., Jones, Z. J. R., Harms, M., Raup, D., Watson, J., Cavaliere, E., and Ho, P. S. (2005) "How sequence defines structure: A crystallographic map of DNA structure and conformation", Proc. Natl. Acad. Sci., USA, 102: 7157-7162.
Hays, F. A., Schirf, V., Ho, P.S., and Demeler, B. (2006) "Solution formation of Holliday junctions in inverted-repeat sequences", Biochemistry, 45: 2467-2471 (Accelerated Communication, "Hot Article" designation, "Top 20 most accessed papers, 2006").
Khuu, P., Voth, A. R., Hays, F. A., and Ho, P. S. (2006) "The stacked-X DNA Holliday junction and protein recognition", J. Mol. Recog. 19: 234-242.
Voth, A. R., Franklin A. Hays, F. A. and Ho, P. S. (2007) "Directing macromolecular Conformation through Halogen Bonds", Proc. Natl. Acad. Sci., USA, 104: 6188-6193 (From the cover & In this Issue feature).
Voth, A. R. and Ho, P. S. (2007) "The role of halogen bonding in inhibitor recognition and binding by protein kinases", Curr. Topics Med. Chem., 7: 1336-1348.
Khuu, P., Sandor, M., DeYoung, J., and Ho, P. S. (2007) "Phylogenomic analysis of the emergence of GC-rich elements", Proc. Natl. Acad. Sci., USA, in press.
K. E. van Holde, W. C. Johnson, and P. S. Ho (2005) Principles of Physical Biochemistry, 2nd Ed. (Prentice Hall, Upper Saddle River, NJ).
NIH PubMed publications list for P. Shing Ho
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Mailing Address:
Dept of Biochemistry and Molecular Biology 1870
Colorado State University
Fort Collins, CO 80523-1870
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