Department of Molecular Medicine
Faculty, Graduate Program
A major focus of our group is to understand the mechanism of action of small molecule ligands — how they change the structure and conformational dynamics of the proteins they target and how this contributes to biological function.
Our targets of interest are nuclear receptors, which are ligand-responsive transcriptional regulators with important roles in embryonic development, organ physiology, cell differentiation, metabolism and homeostasis. Because of their critical role in the development and progression of many human diseases, nuclear receptors are a primary target for pharmaceutical drug discovery, as well as chemical biology efforts to better define their function in vivo.
The binding of ligands causes allosteric conformational changes in the receptors that contribute to their stability, association with chaperones, translocation to the nucleus, DNA binding, posttranslational modification, and recruitment of transcriptional coregulator proteins — combined, these events regulate the recruitment of additional transcriptional machinery to target gene promoters, modulating the expression of target genes.
Using biomolecular NMR spectroscopy, as well as other structural, biophysical and functional techniques, we are working to understand the structural and dynamic mechanism of action of validated nuclear receptor drugs. We have also initiated a combined structural and chemical biology approach towards orphan nuclear receptors, for which no physiological ligands are known. A major goal is to understand how ligand-regulated conformational dynamics contributes to the recruitment of coregulator proteins, critical posttranslational modifications, the overall function of NRs, and the pharmacological phenotype of the ligand — and how these changes may be exploited for purposes of pharmaceutical drug design.
B.S., Chemistry, Purdue University, 2000
Ph.D., Biochemistry, North Carolina State University, 2005
Postdoctoral fellow (2005-2009), University of Cincinnati, Cincinnati, OH
Postdoctoral fellow (2009-2010), The Scripps Research Institute, Jupiter, FL
American Foundation for Aging Research Fellowship (2002-2003)
A.R. Main-Becton Dickinson Graduate Achievement Award (2003)
Gamma Sigma Delta (2003) NIH postdoctoral fellow (2005-2008)
James & Esther King New Investigator Research Award (2010-2013)
Marciano DP, Kuruvilla DS, Boregowda SV, Asteian A, Hughes TS, Garcia-Ordonez R, Corzo CA, Khan TM, Novick SJ, Park H, Kojetin DJ, Phinney DG, Bruning JB, Kamenecka TM, and Griffin PR. (2015) Pharmacological repression of PPARgamma promotes osteogenesis. Nature Communications 6, 7443
Nwachukwu JC, Srinivasan S, Bruno NE, Parent AA, Hughes TS, Pollock JA, Gjyshi O, Cavett V, Nowak J, Garcia-Ordonez RD, Houtman R, Griffin PR, Kojetin DJ, Katzenellenbogen JA, Conkright MD, and Nettles KW. (2014) Resveratrol modulates the inflammatory response via an estrogen receptor-signal integration network. eLife 3, e02057
Matta-Camacho E, Banerjee S, Hughes TS, Solt LS, Wang Y, Burris TP, Kojetin DJ (2014) Structure of REV-ERBb Ligand-Binding Domain Bound to a Porphyrin Antagonist. Journal of Biological Chemistry, 289, 20054-20066
Nwachukwu JC, Srinivasan S, Bruno NE, Parent AA, Hughes TS, Pollock JA, Gjyshi O, Cavett V, Nowak J, Garcia-Ordonez RD, Houtman R, Griffin PR, Kojetin DJ, Katzenellenbogen JA, Conkright MD, Nettles KW (2014) Resveratrol modulates the inflammatory response via estrogen receptor-signal integration network. eLife Apr 25;3:e02057 (doi: 10.7554/eLife.02057)
Hudson WH, Pickard MR, de Vera IM, Kuiper EG, Mourtada-Maarabouni M, Conn GL, Kojetin DJ, Williams GT, and Ortlund EA. (2014) Conserved sequence-specific lincRNA-steroid receptor interactions drive transcriptional repression and direct cell fate. Nature Communications 5, 5395
Hughes TS, Giri PK, de Vera IMS, Marciano DP, Kuruvilla DS, Shin Y, Blayo A, Kamenecka TM, Burris TP, Griffin PR, Kojetin DJ (2014) An alternate binding site for PPARγ ligands. Nature Communications 5, 3571 (DOI: 10.1038/ncomms4571)
Kojetin DJ, Burris TP. (2014) REV-ERB and ROR Nuclear Receptors as Drug Targets. Nature Reviews Drug Discovery 13(3), 197-216.
Burris TP, Solt LA, Wang Y, Crumbley C, Banerjee S, Griffett K, Lundasen T, Hughes T, Kojetin DJ. (2013) Nuclear receptors and their selective pharmacologic modulators. Pharmacological Reviews 65(2), 710-78.
Srinivasan S, Nwachukwu JC, Parent AA, Cavett V, Nowak J, Hughes TS, Kojetin DJ, Katzenellenbogen JA, Nettles KW (2013) Ligand-binding dynamics rewire cellular signaling via estrogen receptor-α. Nature Chemical Biology 9(5), 326-32.
Kojetin DJ#, Burris TP (2013) Small molecule modulation of nuclear receptor conformational dynamics: implications for function and drug discovery. Molecular Pharmacololgy 83(1), 1-8.
Solt LA, Wang Y, Banerjee S, Hughes T, Kojetin DJ, Lundasen T, Shin Y, Liu J, Cameron MD, Noel R, Yoo S-H, Takahashi JS, Butler A, Kamenecka TM and Burris TP. (2012) Regulation of Circadian Behavior and Metabolism by Synthetic REV-ERB Agonists. Nature 485, 7396, 62-8.
Hughes TS, Chalmers MJ, Novick S, Kuruvilla DS, Chang MR, Kamenecka TM, Rance M, Johnson BA, Burris TP, Griffin PR, Kojetin DJ. (2012) Ligand and receptor dynamics contribute to the mechanism of graded PPARγ agonism. Structure 20, 1, 139-50.
Featured preview article: Yu E, Xu He. (2012) Couple Dynamics: PPARγ and Its Ligand Partners. Structure 20, 1, 2-4. Abstract: Ligand-regulated transcriptional activity is the most important property of nuclear receptors, including PPARγ. In this issue of Structure, Hughes et al. determined how the dynamic conformations of ligands and the receptor contribute to the degree of ligand-dependent activation of PPARγ, which provide further insights into design of PPARγ-based anti-diabetic drugs.
Zhang J, Chalmers MJ, Stayrook KR, Burris LL, Wang Y, Busby SA, Pascal BD, Garcia-Ordonez RD, Bruning JB, Istrate MA, Kojetin DJ, Dodge JA, Burris TP, Griffin PR. (2011) DNA binding alters coactivator interaction surfaces of the intact VDR-RXR complex. Nat. Struct. Mol. Biol. 18, 5, 556-63.
Kojetin D, Wang Y, Kamenecka TM, Burris TP. (2011) Identification of SR8278, a synthetic antagonist of the nuclear heme receptor REV-ERB. ACS Chem. Biol. 6, 2, 131-4.