Mark A. Rould, PhD
Assistant Research Professor, Molecular Physiology and Biophysics
Director, UVM Center for X-Ray Crystallography
Faculty Member, Cell and Molecular Biology Program
Faculty Member, Vermont Cancer Center
BS*2 1984 Biochemistry & Cellular and Developmental Biology, University of Arizona;
PhD 1991 Molecular Biophysics and Biochemistry, Yale University;
Specialist in Research 1991-1998 Macromolecular Crystallography, Massachusetts Institute of Technology.
Understanding how molecules small and large are recognized by proteins, and how their binding can elicit changes in protein structure, is the central theme tying the broad spectrum of projects pursued in our lab. We forge and wield new tools in the field of X-Ray Crystallography to decipher the molecular basis of natural and exogenous ligand binding, and the propagation of conformational change. For example, collaborative projects with Kathy Trybus and Susan Lowey are aimed at visualizing the pathway by which changes in the nucleotide state of motor proteins such as kinesin, myosin and actin are coupled to the conformational changes ultimately responsible for the biological generation of force. Visualizing at atomic resolution the molecular choreography involved in DNA recombination and DNA repair are also key collaborative projects with Scott Morrical, Sylvie Doublie and Susan Wallace. In collaboration with UVM chemist Jose Madalengoitia, we have developed and are applying a high-throughput crystallographic approach to detect and characterize protein-ligand interactions from within extensively diverse combinatorial libraries of organic compounds, as a means to accelerate the search for pharmaceutical leads, prescreen for potentially toxic interactions, and determine the function of crystallized proteins of unknown function from the constellation of bound exogenous compounds.
Rould, M.A., Perona, J.J., Soll, D., Steitz, T.A. (1989) Structure of E. coli glutaminyl-tRNA synthetase complexed with tRNAGln and ATP at 2.8Å resolution. Science 246, 1135-1142.
Perona, J.J., Swanson, R., Rould, M.A., Steitz, T.A., Soll, D. (1989) Structural basis for misaminoacylation by mutant E. coli glutaminyl-tRNA synthetase enzymes. Science 246, 1152-1154.
Perona, J.J., Rould, M.A., Steitz, T.A., Risler, J.-L., Zelwer, C., Brunie, S. (1991) Structural similarities in glutaminyl- and methionyl-tRNA synthetase suggest a common overall orientation of tRNA binding. Proc. Natl. Acad. Sci. USA 88, 2903-2907.
Rould, M.A., Perona, J.J., Steitz, T.A. (1991) Structural basis of anticodon loop recognition by glutaminyl-tRNA synthetase. Nature 352, 213-218.
Rould, M.A., Steitz, T.A. (1992) Structure of the glutaminyl-tRNA synthetase - tRNAGln - ATP complex. In: Nucleic Acids and Molecular Biology Vol. 6 (F. Eckstein, D.M.J. Lilley, eds.) Springer-Verlag, New York, pp. 225-246.
Rould, M.A., Perona, J.J., Steitz, T.A. (1992) Improving MIR phasing by heavy atom refinement using solvent-flattened phases. Acta Cryst. A48, 751-756.
Perona, J.J., Rould, M.A., Steitz, T.A. (1993) Structural basis for tRNA aminoacylation by E. coli glutaminyl-tRNA synthetase. Biochemistry 32, 8758-8771.
Raumann, B.E., Rould, M.A., Pabo, C.O. & Sauer, R.T. (1994) DNA Recognition by Beta-sheets in the Arc Repressor-Operator Crystal Structure. Nature 367,754-757.
Klemm, J.D., Rould, M.A., Aurora, R., Herr, W. & Pabo, C.O. (1994) Crystal Structure of the Oct-1 POU Domain Bound to an Octamer Site: DNA Recognition with Tethered DNA-Binding Modules. Cell 77, 21-32.
Ma, P.C., Rould, M.A., Weintraub, H., and Pabo, C.O. (1994) Crystal Structure of MyoD bHLH Domain Bound to DNA: New Perspectives on DNA Recognition and Transcriptional Activation. Cell 77, 451-459.
Landes, C., Perona, J.J., Brunie, S., Rould, M.A., Zelwer, C., Steitz, T.A., Risler, J.-L. (1995) A structure-based multiple sequence alignment of all class I aminoacyl-tRNA synthetases. Biochimie 77, 194-203.
Xu, W., Rould, M.A., Jun, S., Desplan, C., Pabo, C.O. (1995) Crystal Structure of a Paired Domain-DNA Complex at 2.5A Resolution Reveals Structural Basis for Pax Developmental Mutations. Cell 80, 639-650.
Elrod-Erickson, M., Rould, M.A., Nekludova, L., Pabo, C.O. (1996) Zif268 protein-DNA Complex Refined at 1.6A : A Model System for Understanding Zinc-Finger DNA Interactions. Structure 4, 1171-1180.
Rould, M.A. (1997) Screening for Heavy-Atom Derivatives and Obtaining Accurate Isomorphous Differences. Methods in Enzymology 276, 461-472.
Tucker-Kellogg, L., Rould, M.A., Chambers, K.A., Ades, S.E, Sauer, R.T., Pabo, C.O. (1997) Engrailed (Gln50-->Lys) Homeodomain-DNA Complex at 1.9 Resolution : Structural Basis for Enhanced Affinity and Altered Specificity. Structure 5, 1047-1054.
Fraenkel, E., Rould, M.A., Chambers, K.A., Pabo, C.O. (1998) Engrailed Homeodomain-DNA Complex at 2.2_ Resolution: A detailed view of the interface and comparison with other engrailed structures. J. Mol. Biol. 284, 351-361.
Xu, H.E., Rould, M.A., Xu, W., Epstein, J., Maas, R.L., Pabo, C.O. (1999)
Crystal Structure of the Human PAX6 Paired Domain-DNA complex reveals specific roles for the linker region and carboxy-terminal subdomain in DNA binding. Genes and Dev. 13:1263-1275.
Ohndorf, U.-M., Rould, M.A., He, Q., Pabo, C.O., Lippard, S.J. (1999) Molecular basis for recognition of cisplatin-modified DNA by high-mobility group proteins. Nature 399:708-712.
Schwartz, T., Rould, M.A., Lowenhaupt, K., Herbert, A., Rich, A. (1999) Crystal structure of the Z-alpha domain of ADAR1 bound to left-handed Z-DNA. Science 284:1841-1845.
Grant, R.A., Rould, M.A., Klemm, J.D., Pabo, C.O. (2000) Exploring the role of glutamine 50 in the homeodomain-DNA interface: Crystal structure of engrailed (Gln50-->Ala) complex at 2.0Å. Biochemistry, 39, 8187-8192.
Rould, M.A., Carter, C.W. Jr. (2003) Isomorphous Difference Methods. Methods in Enzymology 374, 145-163.
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