Graduate students in biochemistry and chemical biology meld molecular and structural biology with physical, organic and analytical chemistry to understand the molecular basis of life. Research in the Biochemistry and Chemical Biology Division focuses on the structure and function of proteins, membranes, DNA, RNA, large macromolecular complexes and viruses.
Students are a constant source of new hypotheses for mechanisms underlying cellular machines like the ribosome and spliceosome, and for the protein and RNA folding problems. Students tackle these problems using biochemical methods, chemical biosensor technologies, protein and nucleic acid crystallography, multi-dimensional NMR spectroscopy, surface chemistry, atomic force microscopy and fluorescence spectroscopy.
Our work also includes major efforts directed towards understanding the molecular basis of disease. Doctoral students leave the Department broadly trained for leadership roles in academia and industry.
As published in the Journal of Molecular Biology, in collaboration with researchers from UNC's Department of Biology, investigators in the Redinbo Group show how the majority of eukaryotic pre-mRNAs are processed by 3'-end cleavage and polyadenylation. The complex responsible contains the ~1160-residue protein Symplekin. The structure and dynamics of the Symplekin N-terminal HEAT domain were investigated to begin elucidating the role Symplekin plays in mRNA maturation. The crystal structure of the Drosophila melanogaster Symplekin HEAT domain was determined to 2.4 Å resolution with single-wavelength anomalous dispersion phasing methods.
Molecular dynamics simulations of this domain show that the presence of a unique loop dampens correlated and anticorrelated motion in the HEAT domain, therefore providing a neutral surface for potential protein–protein interactions. HEAT domains are often employed for such macromolecular contacts. Together, these data support the conclusion that the Symplekin HEAT domain serves as a scaffold for protein–protein interactions essential to the mRNA maturation process.
Cellular RNA molecules undergo complex folding transitions to form specific, biologically active, three-dimensional structures. A persistent and poorly explained observation is that many RNAs fold very slowly, on timescales requiring minutes or longer. Slow folding ultimately governs the rate at which an RNA can perform its biological function.
In work reported in PNAS, Stefanie Mortimer in the Weeks Lab used time-resolved SHAPE chemistry to show that slow folding at a single nucleotide in the unusual C2'-endo conformation constitutes the rate-determining step for folding a large 50 kDa RNA. Nucleotides in the C2'-endo conformation are relatively rare but are highly overrepresented in functionally critical RNA motifs. This work thus identifies a surprisingly simple, but likely ubiquitous, mechanism for controlling biological processes involving RNA.
A Synthetic Receptor for Asymmetric Dimethyl Arginine. Lindsey I. James , Joshua E. Beaver , Natalie W. Rice , and Marcey L. Waters. J. Am. Chem. Soc., 2013, 135 (17), pp 6450–6455.
Long-Range Architecture in a Viral RNA Genome. Eva J. Archer, Mark A. Simpson, Nicholas J. Watts, Rory O'Kane, Bangchen Wang, Dorothy A. Erie, Alex McPherson, and Kevin M. Weeks. Biochemistry, 2013, 52 (18), pp 3182–3190.
A Guanosine-Centric Mechanism for RNA Chaperone Function. Jacob K. Grohman, Robert J. Gorelick, Colin R. Lickwar, Jason D. Lieb, Brian D. Bower, Brent M. Znosko, Kevin M. Weeks. http://www.sciencemag.org/content/early/2013/03/06/science.1230715.
Molecular Basis of Antibiotic Multiresistance Transfer in Staphylococcus aureus. Jonathan S. Edwards, Laurie Betts, Monica L. Frazier, Rebecca M. Pollet, Stephen M. Kwong, William G. Walton, W. Keith Ballentine III, Julianne J. Huang, Sohrab Habibi, Mark Del Campo, Jordan L. Meier, Peter. B. Dervan, Neville Firth, and Matthew R. Redinbo. PNAS January 28, 2013, Published online before print DOI: 10.1073/pnas.1219701110.
Olefin Cyclopropanation via Carbene Transfer Catalyzed by Engineered Cytochrome P450 Enzymes. Pedro S. Coelho, Eric M. Brustad, Arvind Kannan, Frances H. Arnold. Science DOI: 10.1126/science.1231434.
Unexpected Effects of Macromolecular Crowding on Protein Stability. Laura A. Benton, Austin E. Smith, Gregory B. Young, and Gary J. Pielak . Biochemistry, Article ASAP, DOI: 10.1021/bi300909q, Publication Date (Web): November 20, 2012.
Macromolecular Crowding and Protein Stability. Yaqiang Wang, Mohona Sarkar, Austin E. Smith, Alexander S. Krois, and Gary J. Pielak . J. Am. Chem. Soc., 2012, 134 (40), pp 16614–16618.
Development of a Peptidase-Resistant Substrate for Single-Cell Measurement of Protein Kinase B Activation. Angela Proctor, Qunzhao Wang, David S. Lawrence, and Nancy L. Allbritton. Anal. Chem., 2012, 84 (16), pp 7195–7202.
Merging of Confocal and Caging Technologies: Selective Three-Color Communication with Profluorescent Reporters. Melanie Priestman, Thomas Shell, Liang Sun, Hsien-Ming Lee, David Lawrence. Angewandte Chemie International Edition, Volume 51, Issue 31, pages 7684–7687, July 27, 2012.
Low Modulus Biomimetic Microgel Particles with High Loading of Hemoglobin. Kai Chen, Timothy J. Merkel, Ashish Pandya, Mary E. Napier, J. Christopher Luft, Will Daniel, Sergei Sheiko, and Joseph M. DeSimone. Biomacromolecules, Article ASAP, DOI: 10.1021/bm3007242, Online August 1, 2012.