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Douglas Kojetin, Ph.D.

Associate Professor
Department of Integrative Structural and Computational Biology
Florida Campus
Laboratory Website
Scripps VIVO Scientific Profile
dkojetin@scripps.edu
(561) 228-2298

Scripps Research Joint Appointments

Department of Molecular Medicine
Faculty, Graduate Program

Research Focus

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.

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

All Publications

de Vera IMS, Zheng J, Novick S, Shang J, Hughes TS, Brust R, Munoz-Tello P, Gardner WJ Jr, Marciano DP, Kong X, Griffin PR, Kojetin DJ. Synergistic Regulation of Coregulator/Nuclear Receptor Interaction by Ligand and DNA. Structure. 2017 Aug 23. pii: S0969-2126(17)30253-8. doi: 10.1016/j.str.2017.07.019. [Epub ahead of print] PMID: 28890360

Weikum ER, de Vera IMS, Nwachukwu JC, Hudson WH, Nettles KW, Kojetin DJ, Ortlund EA. Tethering not required: the glucocorticoid receptor binds directly to activator protein-1 recognition motifs to repress inflammatory genes. Nucleic Acids Res. 2017 Aug 21;45(14):8596-8608. doi:10.1093/nar/gkx509. PMID: 28591827

Brust R, Lin H, Fuhrmann J, Asteian A, Kamenecka TM, Kojetin DJ. Modification of the Orthosteric PPARγ Covalent Antagonist Scaffold Yields an ImprovedDual-Site Allosteric Inhibitor. ACS Chem Biol. 2017 Apr 21;12(4):969-978. doi:10.1021/acschembio.6b01015. Epub 2017 Feb 16. PubMed PMID: 28165718.

Nwachukwu JC, Srinivasan S, Bruno NE, Nowak J, Wright NJ, Minutolo F, Rangarajan ES, Izard T, Yao XQ, Grant BJ, Kojetin DJ, Elemento O, Katzenellenbogen JA, Nettles KW. Systems Structural Biology Analysis of Ligand Effects on ERα Predicts Cellular Response to Environmental Estrogens and Anti-hormone Therapies. Cell Chem Biol. 2017 Jan 19;24(1):35-45. doi: 10.1016/j.chembiol.2016.11.014. Epub 2016 Dec 29. PubMed PMID: 28042045.

Hughes TS, Shang J, Brust R, de Vera IM, Fuhrmann J, Ruiz C, Cameron MD, Kamenecka TM, Kojetin DJ. Probing the Complex Binding Modes of the PPARγ Partial Agonist 2-Chloro-N-(3-chloro-4-((5-chlorobenzo[d]thiazol-2-yl)thio)phenyl)-4-(trifluoromethyl)benzenesulfonamide (T2384) to Orthosteric and Allosteric Sites with NMR Spectroscopy. J Med Chem. 2016 Nov 23;59(22):10335-10341. Epub 2016 Nov 4. PubMed PMID: 27783520; PubMed Central PMCID: PMC5179221.

Hudson WH, Kossmann BR, de Vera IM, Chuo SW, Weikum ER, Eick GN, Thornton JW, Ivanov IN, Kojetin DJ, Ortlund EA. Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformational space. Proc Natl Acad Sci U S A. 2016 Jan 12;113(2):326-31. doi: 10.1073/pnas.1518960113. Epub 2015 Dec 29. PubMed PMID: 26715749; PubMed Central PMCID: PMC4720311.

Fuhrmann J, Subramanian V, Kojetin DJ, Thompson PR. Activity-Based Profiling Reveals a Regulatory Link between Oxidative Stress and Protein Arginine Phosphorylation. Cell Chem Biol. 2016 Aug 18;23(8):967-977. doi:10.1016/j.chembiol.2016.07.008. Epub 2016 Aug 11. PubMed PMID: 27524296; PubMed Central PMCID: PMC5157131.

Hepowit NL, de Vera IM, Cao S, Fu X, Wu Y, Uthandi S, Chavarria NE, Englert M, Su D, Sӧll D, Kojetin DJ, Maupin-Furlow JA. Mechanistic insight into protein modification and sulfur mobilization activities of noncanonical E1 and associated ubiquitin-like proteins of Archaea. FEBS J. 2016 Oct;283(19):3567-3586. doi: 10.1111/febs.13819. PubMed PMID: 27459543; PubMed Central PMCID: PMC5053900.

de Vera IM, Giri PK, Munoz-Tello P, Brust R, Fuhrmann J, Matta-Camacho E, Shang J, Campbell S, Wilson HD, Granados J, Gardner WJ Jr, Creamer TP, Solt LA, Kojetin DJ. Identification of a Binding Site for Unsaturated Fatty Acids in the Orphan Nuclear Receptor Nurr1. ACS Chem Biol. 2016 Jul 15;11(7):1795-9. doi: 10.1021/acschembio.6b00037. Epub 2016 Apr 29. PubMed PMID: 27128111; PubMed Central PMCID: PMC4946999.

Thenin-Houssier S, de Vera IM, Pedro-Rosa L, Brady A, Richard A, Konnick B, Opp S, Buffone C, Fuhrmann J, Kota S, Billack B, Pietka-Ottlik M, Tellinghuisen T, Choe H, Spicer T, Scampavia L, Diaz-Griffero F, Kojetin DJ, Valente ST. Ebselen, a Small-Molecule Capsid Inhibitor of HIV-1 Replication. Antimicrob Agents Chemother. 2016 Mar 25;60(4):2195-208. doi: 10.1128/AAC.02574-15. Print 2016 Apr. PubMed PMID: 26810656; PubMed Central PMCID: PMC4808204.

Kojetin DJ, Matta-Camacho E, Hughes TS, Srinivasan S, Nwachukwu JC, Cavett V, Nowak J, Chalmers MJ, Marciano DP, Kamenecka TM, Shulman AI, Rance M, Griffin PR, Bruning JB, Nettles KW. Structural mechanism for signal transduction in RXR nuclear receptor heterodimers. Nat Commun. 2015 Aug 20;6:8013. doi: 10.1038/ncomms9013. PubMed PMID: 26289479; PubMed Central PMCID: PMC4547401.

Hughes TS, Wilson HD, de Vera IM, Kojetin DJ. Deconvolution of Complex 1D NMR Spectra Using Objective Model Selection. PLoS One. 2015 Aug 4;10(8):e0134474. doi: 10.1371/journal.pone.0134474. eCollection 2015. PubMed PMID: 26241959; PubMed Central PMCID: PMC4524620.

Wang Y, Kojetin D, Burris TP. Anti-proliferative actions of a synthetic REV-ERBα/β agonist in breast cancer cells. Biochem Pharmacol. 2015 Aug 15;96(4):315-22. doi: 10.1016/j.bcp.2015.06.010. Epub 2015 Jun 12. PubMed PMID: 26074263; PubMed Central PMCID: PMC4526361.

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 IM, Marciano DP, Kuruvilla DS, Shin Y, Blayo AL,Kamenecka TM, Burris TP, Griffin PR, Kojetin DJ. An alternate binding site for PPARγ ligands. Nat Commun. 2014 Apr 7;5:3571. doi: 10.1038/ncomms4571. PubMed PMID: 24705063; PubMed Central PMCID: PMC4070320.

Kojetin DJ, Burris TP. REV-ERB and ROR nuclear receptors as drug targets. Nat Rev Drug Discov. 2014 Mar;13(3):197-216. doi: 10.1038/nrd4100. Review. PubMedPMID: 24577401; PubMed Central PMCID: PMC4865262. 

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, KojetinDJ, Katzenellenbogen JA, Nettles KW. Ligand-binding dynamics rewire cellularsignaling via estrogen receptor-α. Nat Chem Biol. 2013 May;9(5):326-32. doi:10.1038/nchembio.1214. Epub 2013 Mar 24. PubMed PMID: 23524984; PubMed CentralPMCID: PMC3631275. 

Kojetin DJ and 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.

Links

Scripps Florida Scientists’ Structural Discoveries Could Aid in Better Drug Design

Scripps Florida Scientists Uncover Startling New Functional Details of Common Anti-Diabetic Drugs

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