Scripps Research Joint Appointments

Faculty, Kellogg School of Science and Technology
Faculty, Kellogg School of Science and Technology

Research Focus

A major focus of our group is to understand how the structure and conformational dynamics of biomolecular complexes contribute to their biological function. We are particularly interested in how ligands (natural small molecules and synthetic chemical probes) modulate the function of nuclear receptor (NR) transcriptional complexes.

NRs 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, NRs 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 (PTM), 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 determine how NR ligands change the structure and conformational dynamics of NR transcriptional complexes. The major goal is to understand how conformational dynamics contributes in the recruitment of coregulator proteins, critical PTMs, 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.

Education

B.S., Chemistry, Purdue University, 2000
Ph.D., Biochemistry, North Carolina State University, 2005

Professional Experience

Postdoctoral fellow (2005-2009), University of Cincinnati, Cincinnati, OH
Postdoctoral fellow (2009-2010), The Scripps Research Institute, Jupiter, FL

Awards & Professional Activities

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)

Selected References

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.

Solt LA, Kojetin DJ, Burris TP. (2011) The REV-ERBs and RORs: molecular links between circadian rhythms and lipid homeostasis. Future Med. Chem. 3, 5, 623-38.

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 DJ, Burris TP. (2011) A role for rev-erbα ligands in regulation of adipogenesis. Curr. Pharm. Des. 17, 4, 320-4.

Kumar N, Kojetin DJ, Solt LA, Kumar KG, Nuhant P, Duckett DR, Cameron MD, Butler AA, Roush WR, Griffin PR, Burris TP. (2011) Identification of SR3335 (ML-176): a synthetic RORα selective inverse agonist. ACS Chem. Biol. 6, 3, 218-22.

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.

Crumbley C, Wang Y, Kojetin DJ, Burris TP (2010) Characterization of the core mammalian clock component, NPAS2, as a REV-ERBα/RORα target gene. J. Biol. Chem. 285, 46, 35386-92.

Kojetin DJ, McLaughlin PD, Thompson R, Dubnau D, Prepiak P, Rance M, Cavanagh J (2009) Structural and motional contributions of the Bacillus subtilis ClpC N-domain in adaptor protein interactions. J. Mol. Biol. 387, 639-52.

Sullivan D, Bobay BG, Kojetin DJ, Thompson R, Rance M, Strauch MA, Cavanagh J (2008) Insights into the nature of DNA-binding of AbrB-like transcription factors. Structure 16, 1702-13.

Kojetin DJ, Venters RA, Kordys DR, Thompson R, Kumar R, Cavanagh J (2006) Structure, binding interface and hydrophobic transitions of Ca²⁺ -loaded calbindin-D_28K. Nat. Struct. Mol. Biol. 13, 641-7.

Links

Couple Dynamics: PPARg and Its Ligand Partners

Scripps Research Scientists Paint New Picture of Dance Between Protein and Binding Partners

Scripps Research Scientists Share $2 Million in Florida State Research Grants

Scripps Research Appoints Douglas Kojetin to Florida Faculty