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Integrative Structural and Computational Biology

Douglas Kojetin, PhD

Associate Professor
Department of Integrative Structural and Computational Biology
Florida Campus
Laboratory Website
(561) 228-2298

Scripps Research Joint Appointments

Department of Integrative Structural and Computational Biology
Department of Molecular Medicine

Research Focus

Nuclear receptors are ligand-regulated transcription factors that control nearly all aspects of human physiology. Nuclear receptor function is linked to physiological processes that regulate human disease under normal and aberrant conditions including cardiovascular, metabolic, and neurological disorders, cancer, and inflammation. The ligand-regulated nature of nuclear receptor function has provided opportunities to develop synthetic ligands to pharmacologically probe the function of nuclear receptors in normal and diseased states, which has provided therapeutic treatments for a variety of disorders including ~16% of FDA approved drugs.

The goal of our research is to understand how activation and repression of nuclear receptor transcription is regulated on the structural and molecular level, including the influence of small molecule ligands—natural/endogenous ligands, synthetic ligands, and FDA-approved drugs used clinically. We use biomolecular NMR spectroscopy as a main structural technique, but also apply a variety of structural, computational, biophysical, and functional approaches including X-ray crystallography, molecular dynamics simulations, biophysical and biochemical assays, and cellular assays to connect molecular and structural findings to cellular functions. 


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

Chen ML, Huang X, Wang H, Hegner C, Liu Y, Shang J, Eliason A, Diao H, Park H, Frey B, Wang G, Mosure SA, Solt LA, Kojetin DJ, Rodriguez-Palacios A, Schady DA, Weaver CT, Pipkin ME, Moore DD, Sundrud MS. CAR directs T cell adaptation to bile acids in the small intestine. Nature. 2021;593(7857):147-151. doi: 10.1038/s41586-021-03421-6. Epub 2021 Apr 7. PMID: 33828301. [pubmed] [journal] [bioRxiv prior to journal submission]

Mosure SA, Strutzenberg TS, Shang J, Munoz-Tello P, Solt LA, Griffin PR, Kojetin DJ. Structural basis for heme-dependent NCoR binding to the transcriptional repressor REV-ERBβ. Science Advances 2021;7(5):eabc6479 [pubmed] [journal] [bioRxiv version prior to journal submission]

Bruno NE, Nwachukwu JC, Srinivasan S, Nettles CC, Izard T, Jin Z, Nowak J, Cameron MD, Boregowda SV, Phinney DG, Elemento O, Liu X, Ortlund EA, Houtman R, Stavreva DA, Hager GL, Kamenecka TM, Kojetin DJ, Nettles KW. Chemical Systems Biology Reveals Mechanisms of Dissociated Glucocorticoid Receptor Signaling. Nature Chemical Biology 2021;17(3):307-316  [pubmed] [journal] [bioRxiv version prior to journal submission]

Munoz-Tello P, Lin H, Khan P, Kamenecka TM, Kojetin DJ. Assessment of NR4A Ligands that Directly Bind and Modulate the Orphan Nuclear Receptor Nurr1. Journal of Medicinal Chemistry 2020;63(24):15639-15654 [pubmed] [journal] [bioRxiv version prior to journal submission]

Shang J, Mosure SA, Zheng J, Brust R, Bass J, Nichols A, Solt KA, Griffin PR, Kojetin DJ. A Molecular Switch Regulating Transcriptional Repression and Activation of PPARγ. Nature Communications 2020;11(1):956. [pubmed] [journal]

Shang J, Brust R, Griffin PR, Kamenecka TM, Kojetin DJ. Quantitative Structural Assessment of Graded Receptor Agonism. PNAS Oct 14; 116(44):22179–22188

Mosure SA, Shang J, Eberhardt J, Brust R, Zheng J, Griffin PR, Forli S,Kojetin DJ. Structural Basis of Altered Potency and Efficacy Displayed by a Majorin Vivo Metabolite of the Antidiabetic PPARγ Drug Pioglitazone. J Med Chem. 2019 Feb 28;62(4):2008-2023. doi: 10.1021/acs.jmedchem.8b01573. Epub 2019 Feb 7.PubMed PMID: 30676741.

Amir M, Chaudhari S, Wang R, Campbell S, Mosure SA, Chopp LB, Lu Q, Shang J, Pelletier OB, He Y, Doebelin C, Cameron MD, Kojetin DJ, Kamenecka TM, Solt LA. REV-ERBα Regulates T(H)17 Cell Development and Autoimmunity. Cell Rep. 2018 Dec 26;25(13):3733-3749.e8. doi: 10.1016/j.celrep.2018.11.101. PubMed PMID: 30590045.

Shang J, Brust R, Mosure SA, Bass J, Munoz-Tello P, Lin H, Hughes TS, Tang M, Ge Q, Kamenekca TM, Kojetin DJ. Cooperative cobinding of synthetic and natural ligands to the nuclear receptor PPARγ. Elife. 2018 Dec 21;7. pii: e43320. doi:10.7554/eLife.43320. PubMed PMID: 30575522; PubMed Central PMCID: PMC6317912.

Patil DN, Rangarajan ES, Novick SJ, Pascal BD, Kojetin DJ, Griffin PR, Izard T, Martemyanov KA. Structural organization of a major neuronal G protein regulator, the RGS7-Gβ5-R7BP complex. Elife. 2018 Dec 12;7. pii: e42150. doi:10.7554/eLife.42150. PubMed PMID: 30540250; PubMed Central PMCID: PMC6310461.

Brust R, Shang J, Fuhrmann J, Mosure SA, Bass J, Cano A, Heidari Z, Chrisman IM, Nemetchek MD, Blayo AL, Griffin PR, Kamenecka TM, Hughes TS, Kojetin DJ. A structural mechanism for directing corepressor-selective inverse agonism of PPARγ. Nat Commun. 2018 Nov 8;9(1):4687. doi: 10.1038/s41467-018-07133-w. PubMed PMID: 30409975; PubMed Central PMCID: PMC6224492.

de Vera IMS, Munoz-Tello P, Zheng J, Dharmarajan V, Marciano DP, Matta-Camacho E, Giri PK, Shang J, Hughes TS, Rance M, Griffin PR, Kojetin DJ. Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1. Structure. 2019 Jan 2;27(1):66-77.e5. doi: 10.1016/j.str.2018.10.002. Epub 2018 Nov 8. PubMed PMID: 30416039; PubMed Central PMCID: PMC6318021.

Zheng J, Corzo C, Chang MR, Shang J, Lam VQ, Brust R, Blayo AL, Bruning JB, Kamenecka TM, Kojetin DJ, Griffin PR. Chemical Crosslinking Mass Spectrometry Reveals the Conformational Landscape of the Activation Helix of PPARγ; a Model for Ligand-Dependent Antagonism. Structure. 2018 Nov 6;26(11):1431-1439.e6. doi: 10.1016/j.str.2018.07.007. Epub 2018 Aug 23. PubMed PMID: 30146169; PubMedCentral PMCID: PMC6221991.

Chrisman IM, Nemetchek MD, de Vera IMS, Shang J, Heidari Z, Long Y, Reyes-Caballero H, Galindo-Murillo R, Cheatham TE 3rd, Blayo AL, Shin Y, Fuhrmann J, Griffin PR, Kamenecka TM, Kojetin DJ, Hughes TS. Defining a conformational ensemble that directs activation of PPARγ. Nat Commun. 2018 May 4;9(1):1794. doi:10.1038/s41467-018-04176-x. PubMed PMID: 29728618; PubMed Central PMCID:PMC5935666.

Hudson WH, Vera IMS, Nwachukwu JC, Weikum ER, Herbst AG, Yang Q, Bain DL, Nettles KW, Kojetin DJ, Ortlund EA. Cryptic glucocorticoid receptor-binding sites pervade genomic NF-κB response elements. Nat Commun. 2018 Apr 6;9(1):1337. doi:10.1038/s41467-018-03780-1. PubMed PMID: 29626214; PubMed Central PMCID:PMC5889392.

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.

Shang J, Kojetin DJ. Structural Mechanism Underlying Ligand Binding and Activation of PPARγ. Structure 2021 Mar 9;S0969-2126(21)00050-2 [pubmed] [journal] [bioRxiv prior to journal submission]

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.


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