Alfonso Mondragón


PhD, Cambridge

Interdisciplinary Biological Sciences Program
Department of Molecular Biosciences

Office Phone: 847.491.7726
Fax: 847.467.1380
Email
Mondragón Lab

Research

The central theme of our work is the understanding of the atomic mechanism of crucial biological macromolecules through a combination of structural and biophysical studies. The goal of our research is to reveal paradigms for understanding fundamental biological processes common to all organisms. 

DNA topoisomerases. One of our major scientific interests is the structure and mechanism of topoisomerases, enzymes responsible for maintaining the topological state of DNA in the cell. The long term goal of our work is to understand the catalytic mechanism of these molecules in atomic detail. DNA topoisomerases are of interest for several reasons: 1) they are responsible for maintaining the topological state of DNA and are involved in a variety of crucial cellular processes, 2) their involvement in key processes has led to the development of drugs that target topoisomerases, 3) topoisomerases catalyze complex reactions that involves cutting and resealing the DNA and passing DNA strands through this break,  4) topoisomerases are excellent examples of complex molecular machines that perform a complicated reaction in the cell, and 5) the structural studies may provide information to develop new chemotherapeutic agents.
We study topoisomerases in a very comprehensive manner using a variety of techniques ranging from x-ray crystallography to single molecule methods with the goal of providing atomic level understanding of their mechanism that includes not only structural but also dynamical information.

Catalytic RNA molecules. A second large research area is the structure and mechanism of long non-coding RNA molecules.  RNA plays a pivotal role in biology as it is involved in many cellular processes. It is also unique amongst nucleic acids in being able to perform functions normally associated with proteins, such as chemical catalysis and translation regulation. One catalytic RNA molecule that we are studying is RNase P.  RNase P is one of only two ribozymes conserved in all three kingdoms of life and is required in the 5' maturation of tRNAs.

When we initiated our studies of RNase P, there was scant structural information on these molecules. Initially, we elucidated the structure of the specificity domain of RNase P from two different types and showed that RNase P has a common structural core that is stabilized through the use of different peripheral elements, an observation that has now been extended to other large RNAs. Later, we elucidated the structure of the entire RNA component from a thermophilic bacterium. More recently, we determined the structure of a ternary complex formed by the RNA component, the protein component, and tRNA. This last structure provided a wealth of information on the way one RNA molecule recognizes another RNA molecule, the mechanism of RNA cleavage by RNase P, and the overall architecture of all RNase Ps. Our structural work has helped make RNase P one of the best characterized catalytic RNA molecules and continues to make RNase P a paradigm for understanding large ribozymes that recognize their substrate in trans and show multiple turnover while also have providing information on general RNA architecture and folding motifs. Moreover, RNase P is thought to be a relic from the RNA world and its complexity increases in higher organisms as more proteins form part of the complex, making RNase P an ideal model to study the evolution from RNA-only molecules to sophisticated ribonucleoprotein complexes. Thus, understanding the mechanism, structure, and architecture of RNase P promises to provide information on many areas of biology ranging from the structure of long non-coding RNAs to the evolution of molecules from the primordial RNA world.

 

Selected Publications

  1. Lima, C.D., Wang, J.C. and Mondragón, A. Three-dimensional structure of the 67K N-terminal fragment of  E. coli DNA topoisomerase I.  Nature, 367, 138-146, 1994.
  2. Grum, V.L., Li, D., MacDonald, R.I. and Mondragón, A. Structures of two repeats of spectrin suggest models of flexibility. Cell, 98, 523-535, 1999.
  3. Mondragón, A. and DiGate, R. Structure of E. coli DNA topoisomerase III, Structure, 7, 1373-1383, 1999.
  4. Changela, A., DiGate, R. and Mondragón, A. Crystal structure of a complex of a type IA DNA topoisomerase with a single-stranded DNA molecule. Nature, 411, 1077-1081, 2001.
  5. Krasilnikov AS, Yang X, Pan T, Mondragón A. 2003. Crystal structure of the specificity domain of ribonuclease P., Nature, 421. 760-764, 2003.
  6. Changela A., Chen K., Xue Y., Holschen J., Outten C.E., O'Halloran T.V. and Mondragón A. Molecular basis of metal-ion selectivity and zeptomolar sensitivity by CueR. Science, 301, 1383-1387, 2003.
  7. Krasilnikov, A.S., Xiao, Y., Pan, T. and Mondragón, A. Basis for Stuctural Diversity in Homologous RNAs, Science, 306, 104-107, 2004.
  8. Kusunoki, H., Minasov, G., MacDonald, R.I., and Mondragón, A. Independent Movement, Dimerization and Stability of Tandem Repeats of Chicken Brain a-Spectrin, J. Mol. Biol., 344, 495-511, 2004.
  9. Torres-Larios A., Swinger K. K., Krasilnikov A. S., Pan T., Mondragón A. Crystal structure of the RNA component of bacterial ribonuclease P. Nature. 437, 584-587, 2005.
  10. Taneja, B., Patel, A., Slesarev, A., and Mondragón, A. Structure of the N-terminal fragment of topoisomerase V reveals a new family of topoisomerases. EMBO J., 25, 398-408, 2006.
  11. Ipsaro JJ, Huang L, and Mondragón, A. Structures of the spectrin-ankyrin interaction binding domains. Blood, 113, 5385-5393, 2009.
  12. Ipsaro, J.J. and Mondragón, A. Structural basis for spectrin recognition by ankyrin. Blood, 115, 4098-5101, 2010.
  13. Reiter, N.J., Osterman, A., Torres-Larios, A., Swinger K. K., Pan T., Mondragón, A. Structure of a bacterial ribonuclease P holoenzyme in complex with tRNA. Nature, 468, 784-789, 2010.
  14. Terekhova K., Gunn K.H., Marko J.F., and Mondragón, A. Bacterial topoisomerase I and topoisomerase III relax supercoiled DNA via distinct pathways. Nucleic Acids Res. 40, 10432-110440, 2012.
  15. Rajan R., Prasad R., Taneja B., Wilson S.H., and Mondragón, A. Identification of one of the apurinic/apyrimidinic lyase active sites of topoisomerase V by structural and functional studies. Nucleic Acids Res. 41, 657-666, 2013.
  16. Philips, S.J., Canalizo-Hernandez, M., Yildirim, I., Schatz, G.C., Mondragón, A., and O'Halloran, T.V., Allosteric transcriptional regulation via changes in the overall topology of the core promoter, Science, 349, 877-881, 2015.

 

Links

View all publications by publications by Alfonso Mondragon listed in the National Library of Medicine (PubMed).

Recent Photos

October 27, 2015