- 3097E Shelby Hall
- (205) 348-0269
BS, 2005, University of Alabama at Birmingham
PhD, 2010, University of California at Berkeley
Postdoctoral Fellow, 2011-2015, Emory University School of Medicine
Structure and mechanism of RNA modification enzymes, RNA-protein interactions, X-ray crystallography
My research group uses X-ray crystallography and other biophysical techniques to understand the mechanisms of substrate specificity and catalysis used by RNA modification enzymes. Following synthesis by RNA polymerase, RNA molecules undergo modifications such as methylation and thionation or isomerizations (pseudouridine) that in turn affect phenomena such as resistance of cells to antibiotics, accuracy in translation of the genetic code and gene regulation. For most RNA modification enzymes, it is not known how they specifically recognize their substrates among the bulk of RNA within the cell. We aim to discover mechanistic themes governing the specificity of these enzymes.
Methyltransferases that modify 23S ribosomal RNA to initiate antibiotic resistance: The active site of the large ribosomal subunit, the peptidyl transferase center (PTC), and its surrounding environment are important targets for antibiotic action. Enzymes, such as erythromycin resistance methyltransferase and chloramphenicol resistance methyltransferase, methylate specific residues adjacent to the PTC to block antibiotic binding and initiate resistance to multiple classes of antibiotics. Despite the importance of these enzymes for healthcare, the mechanisms governing how they specifically recognize their target nucleotide and promote catalysis are not fully known. We aim to understand these mechanisms to aid in developing inhibitors to these resistance enzymes, restoring the functionality of existing antibiotic therapies.
6-methyl adenosine containing messenger RNA: An exciting recent development in gene regulation is the revelation that modification of messenger RNA (mRNA), by creation of 6-methyl adenosine sites, is a widespread method for controlling mRNA fate from yeast to humans. 6-methyl adenosine ‘writer’ and ‘reader’ proteins are now known to methylate at specific mRNA sites and bind specifically to the methylated sites respectively. This newly discovered method of genetic regulation may have significant roles in health and disease. We aim to understand the specificity mechanisms for 6-methyl adenosine ‘writer’ and ‘reader’ proteins and understand the protein-protein interactions that integrate ‘writers’ and ‘readers’ into upstream and downstream cellular pathways.
Dunkle JA, Vinal K, Desai PM, Zelinskaya N, Savic M, West DM, Conn GL, Dunham CM. Molecular recognition and modification of the 30S ribosome by the aminoglycoside-resistance methyltransferase NpmA. Proc Natl Acad Sci U S A. 2014;111(17):6275-80.
McGinnis JL, Dunkle JA, Cate JH, Weeks KM. The mechanisms of RNA SHAPE chemistry. Journal of the American Chemical Society. 2012;134(15):6617-24.
Dunkle JA, Wang L, Feldman MB, Pulk A, Chen VB, Kapral GJ, Noeske J, Richardson JS, Blanchard SC, Cate JH. Structures of the bacterial ribosome in classical and hybrid states of tRNA binding. Science. 2011;332(6032):981-4.
Dunkle JA, Xiong L, Mankin AS, Cate JH. Structures of the Escherichia coli ribosome with antibiotics bound near the peptidyl transferase center explain spectra of drug action. Proc Natl Acad Sci U S A. 2010;107(40):17152-7.
Zhang W, Dunkle JA, Cate JH. Structures of the ribosome in intermediate states of ratcheting. Science. 2009;325(5943):1014-7.