Douglas Kojetin

Douglas Kojetin, Ph.D.

Associate Professor With Tenure

Department: SR-IS&CB-KOJETIN LAB
Business Phone: (561) 228-2298
Business Email: dkojetin@ufl.edu

About Douglas Kojetin

Related Links:
Additional Positions:
Associate Professor with Tenure, Integrative Structural and Computational Biology
2021 – Current · Scripps Research
Associate Professor, Integrative Structural and Computational Biology
2017 – 2021 · Scripps Research
Associate Professor, Molecular Therapeutics
2014 – 2017 · Scripps Research
Assistant Professor, Molecular Therapeutics
2010 – 2014 · Scripps Research
Research Associate, Molecular Therapeutics
2009 – 2010 · Scripps Research
Postdoctoral Fellow
2005 – 2009 · University of Cincinnati

Accomplishments

James & Esther King New Investigator Research Award
2010-2013 · Florida Department of Health
NIAID Training Grant Postdoctoral Fellow
2008 · University of Cincinnati
NIEHS Training Grant Postdoctoral Fellow
2005-2008 · University of Cincinnati
A.R. Main-Becton Dickinson Graduate Achievement Award
2003 · North Carolina State University
Gamma Sigma Delta
2003 · North Carolina State University
Fellowship
2002-2003 · American Foundation for Aging Research

Research Profile

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 ~13% 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.

Open Researcher and Contributor ID (ORCID)

0000-0001-8058-6168

Publications

2022
Phosphatidylserine orchestrates Myomerger membrane insertions to drive myoblast fusion
Proceedings of the National Academy of Sciences. 119(38) [DOI] 10.1073/pnas.2202490119. [PMID] 36095199.
2021
CAR directs T cell adaptation to bile acids in the small intestine
Nature. 593(7857):147-151 [DOI] 10.1038/s41586-021-03421-6. [PMID] 33828301.
2021
Chemical systems biology reveals mechanisms of glucocorticoid receptor signaling
Nature Chemical Biology. 17(3):307-316 [DOI] 10.1038/s41589-020-00719-w. [PMID] 33510451.
2021
Correction to Assessment of NR4A Ligands That Directly Bind and Modulate the Orphan Nuclear Receptor Nurr1
Journal of Medicinal Chemistry. 64(8):5216-5220 [DOI] 10.1021/acs.jmedchem.1c00526.
2021
Structural basis for heme-dependent NCoR binding to the transcriptional repressor REV-ERBβ
Science Advances. 7(5) [DOI] 10.1126/sciadv.abc6479. [PMID] 33571111.
2021
Structural mechanism underlying ligand binding and activation of PPARγ
Structure. 29(9):940-950.e4 [DOI] 10.1016/j.str.2021.02.006. [PMID] 33713599.
2020
A molecular switch regulating transcriptional repression and activation of PPARγ
Nature Communications. 11(1) [DOI] 10.1038/s41467-020-14750-x. [PMID] 32075969.
2020
Assessment of NR4A Ligands That Directly Bind and Modulate the Orphan Nuclear Receptor Nurr1
Journal of Medicinal Chemistry. 63(24):15639-15654 [DOI] 10.1021/acs.jmedchem.0c00894. [PMID] 33289551.
2019
Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1
Structure. 27(1):66-77.e5 [DOI] 10.1016/j.str.2018.10.002. [PMID] 30416039.
2019
Didehydro-Cortistatin A Inhibits HIV-1 by Specifically Binding to the Unstructured Basic Region of Tat.
mBio. 10(1) [DOI] 10.1128/mBio.02662-18. [PMID] 30723126.
2019
PGRMC2 is an intracellular haem chaperone critical for adipocyte function.
Nature. 576(7785):138-142 [DOI] 10.1038/s41586-019-1774-2. [PMID] 31748741.
2019
Quantitative structural assessment of graded receptor agonism.
Proceedings of the National Academy of Sciences of the United States of America. 116(44):22179-22188 [DOI] 10.1073/pnas.1909016116. [PMID] 31611383.
2019
Structural Basis of Altered Potency and Efficacy Displayed by a Major in Vivo Metabolite of the Antidiabetic PPARγ Drug Pioglitazone
Journal of Medicinal Chemistry. 62(4):2008-2023 [DOI] 10.1021/acs.jmedchem.8b01573. [PMID] 30676741.
2019
The Tat inhibitor didehydro-cortistatin A suppresses SIV replication and reactivation.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 33(7):8280-8293 [DOI] 10.1096/fj.201801165R. [PMID] 31021670.
2018
A structural mechanism for directing corepressor-selective inverse agonism of PPARγ
Nature Communications. 9(1) [DOI] 10.1038/s41467-018-07133-w. [PMID] 30409975.
2018
Author response: Cooperative cobinding of synthetic and natural ligands to the nuclear receptor PPARγ
. [DOI] 10.7554/elife.43320.077.
2018
Author response: Structural organization of a major neuronal G protein regulator, the RGS7-Gβ5-R7BP complex
. [DOI] 10.7554/elife.42150.035.
2018
Author response: Structural organization of a major neuronal G protein regulator, the RGS7-Gβ5-R7BP complex
. [DOI] 10.7554/elife.42150.sa2.
2018
Chemical Crosslinking Mass Spectrometry Reveals the Conformational Landscape of the Activation Helix of PPARγ; a Model for Ligand-Dependent Antagonism.
Structure (London, England : 1993). 26(11):1431-1439.e6 [DOI] 10.1016/j.str.2018.07.007. [PMID] 30146169.
2018
Cooperative cobinding of synthetic and natural ligands to the nuclear receptor PPARγ
eLife. 7 [DOI] 10.7554/elife.43320.
2018
Cryptic glucocorticoid receptor-binding sites pervade genomic NF-κB response elements
Nature Communications. 9(1) [DOI] 10.1038/s41467-018-03780-1. [PMID] 29626214.
2018
Defining a conformational ensemble that directs activation of PPARγ
Nature Communications. 9(1) [DOI] 10.1038/s41467-018-04176-x. [PMID] 29728618.
2018
REV-ERBα Regulates TH17 Cell Development and Autoimmunity.
Cell reports. 25(13):3733-3749.e8 [DOI] 10.1016/j.celrep.2018.11.101. [PMID] 30590045.
2018
Structural organization of a major neuronal G protein regulator, the RGS7-Gβ5-R7BP complex
eLife. 7 [DOI] 10.7554/elife.42150.
2017
Modification of the Orthosteric PPARγ Covalent Antagonist Scaffold Yields an Improved Dual-Site Allosteric Inhibitor
ACS Chemical Biology. 12(4):969-978 [DOI] 10.1021/acschembio.6b01015. [PMID] 28165718.
2017
Synergistic Regulation of Coregulator/Nuclear Receptor Interaction by Ligand and DNA.
Structure (London, England : 1993). 25(10):1506-1518.e4 [DOI] 10.1016/j.str.2017.07.019. [PMID] 28890360.
2017
Systems Structural Biology Analysis of Ligand Effects on ERα Predicts Cellular Response to Environmental Estrogens and Anti-hormone Therapies.
Cell chemical biology. 24(1):35-45 [DOI] 10.1016/j.chembiol.2016.11.014. [PMID] 28042045.
2017
Tethering not required: the glucocorticoid receptor binds directly to activator protein-1 recognition motifs to repress inflammatory genes.
Nucleic acids research. 45(14):8596-8608 [DOI] 10.1093/nar/gkx509. [PMID] 28591827.
2016
Activity-Based Profiling Reveals a Regulatory Link between Oxidative Stress and Protein Arginine Phosphorylation.
Cell chemical biology. 23(8):967-977 [DOI] 10.1016/j.chembiol.2016.07.008. [PMID] 27524296.
2016
Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformational space.
Proceedings of the National Academy of Sciences of the United States of America. 113(2):326-31 [DOI] 10.1073/pnas.1518960113. [PMID] 26715749.
2016
Ebselen, a Small-Molecule Capsid Inhibitor of HIV-1 Replication.
Antimicrobial agents and chemotherapy. 60(4):2195-208 [DOI] 10.1128/AAC.02574-15. [PMID] 26810656.
2016
Identification of a Binding Site for Unsaturated Fatty Acids in the Orphan Nuclear Receptor Nurr1.
ACS chemical biology. 11(7):1795-9 [DOI] 10.1021/acschembio.6b00037. [PMID] 27128111.
2016
Mechanistic insight into protein modification and sulfur mobilization activities of noncanonical E1 and associated ubiquitin-like proteins of Archaea.
The FEBS journal. 283(19):3567-3586 [DOI] 10.1111/febs.13819. [PMID] 27459543.
2016
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.
Journal of medicinal chemistry. 59(22):10335-10341 [DOI] 10.1021/acs.jmedchem.6b01340. [PMID] 27783520.
2015
Anti-proliferative actions of a synthetic REV-ERBα/β agonist in breast cancer cells.
Biochemical pharmacology. 96(4):315-22 [DOI] 10.1016/j.bcp.2015.06.010. [PMID] 26074263.
2015
Deconvolution of Complex 1D NMR Spectra Using Objective Model Selection.
PloS one. 10(8) [DOI] 10.1371/journal.pone.0134474. [PMID] 26241959.
2015
Pharmacological repression of PPARγ promotes osteogenesis.
Nature communications. 6 [DOI] 10.1038/ncomms8443. [PMID] 26068133.
2015
Structural mechanism for signal transduction in RXR nuclear receptor heterodimers.
Nature communications. 6 [DOI] 10.1038/ncomms9013. [PMID] 26289479.
2014
An alternate binding site for PPARγ ligands.
Nature communications. 5 [DOI] 10.1038/ncomms4571. [PMID] 24705063.
2014
Conserved sequence-specific lincRNA-steroid receptor interactions drive transcriptional repression and direct cell fate.
Nature communications. 5 [DOI] 10.1038/ncomms6395. [PMID] 25377354.
2014
Resveratrol modulates the inflammatory response via an estrogen receptor-signal integration network.
eLife. 3 [DOI] 10.7554/eLife.02057. [PMID] 24771768.
2014
REV-ERB and ROR nuclear receptors as drug targets.
Nature reviews. Drug discovery. 13(3):197-216 [DOI] 10.1038/nrd4100. [PMID] 24577401.
2014
Structure of REV-ERBβ ligand-binding domain bound to a porphyrin antagonist.
The Journal of biological chemistry. 289(29):20054-66 [DOI] 10.1074/jbc.M113.545111. [PMID] 24872411.
2013
Ligand-binding dynamics rewire cellular signaling via estrogen receptor-α.
Nature chemical biology. 9(5):326-32 [DOI] 10.1038/nchembio.1214. [PMID] 23524984.
2013
Nuclear receptors and their selective pharmacologic modulators.
Pharmacological reviews. 65(2):710-78 [DOI] 10.1124/pr.112.006833. [PMID] 23457206.
2013
Small molecule modulation of nuclear receptor conformational dynamics: implications for function and drug discovery.
Molecular pharmacology. 83(1):1-8 [DOI] 10.1124/mol.112.079285. [PMID] 22869589.
2012
Ligand and receptor dynamics contribute to the mechanism of graded PPARγ agonism.
Structure (London, England : 1993). 20(1):139-50 [DOI] 10.1016/j.str.2011.10.018. [PMID] 22244763.
2012
Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists.
Nature. 485(7396):62-8 [DOI] 10.1038/nature11030. [PMID] 22460951.
2012
Regulation of p53 stability and apoptosis by a ROR agonist.
PloS one. 7(4) [DOI] 10.1371/journal.pone.0034921. [PMID] 22509368.
2012
Small molecule tertiary amines as agonists of the nuclear hormone receptor Rev-erbα.
Bioorganic & medicinal chemistry letters. 22(13):4413-7 [DOI] 10.1016/j.bmcl.2012.04.126. [PMID] 22633688.
2012
Structural and biophysical insights into the ligand-free Pitx2 homeodomain and a ring dermoid of the cornea inducing homeodomain mutant.
Biochemistry. 51(2):665-76 [DOI] 10.1021/bi201639x. [PMID] 22224469.
2012
Synthesis and SAR of tetrahydroisoquinolines as Rev-erbα agonists.
Bioorganic & medicinal chemistry letters. 22(11):3739-42 [DOI] 10.1016/j.bmcl.2012.04.023. [PMID] 22560469.
2012
¹H, ¹³C and ¹⁵N chemical shift assignments for the human Pitx2 homeodomain in complex with a 22-base hairpin DNA.
Biomolecular NMR assignments. 6(1):79-81 [DOI] 10.1007/s12104-011-9329-y. [PMID] 21818549.
2011
1H, 13C and 15N chemical shift assignments for the human Pitx2 homeodomain and a R24H homeodomain mutant.
Biomolecular NMR assignments. 5(1):105-7 [DOI] 10.1007/s12104-010-9278-x. [PMID] 21052876.
2011
A role for rev-erbα ligands in regulation of adipogenesis.
Current pharmaceutical design. 17(4):320-4 [PMID] 21375499.
2011
DNA binding alters coactivator interaction surfaces of the intact VDR-RXR complex.
Nature structural & molecular biology. 18(5):556-63 [DOI] 10.1038/nsmb.2046. [PMID] 21478866.
2011
Identification of SR3335 (ML-176): a synthetic RORα selective inverse agonist.
ACS chemical biology. 6(3):218-22 [DOI] 10.1021/cb1002762. [PMID] 21090593.
2011
Identification of SR8278, a synthetic antagonist of the nuclear heme receptor REV-ERB.
ACS chemical biology. 6(2):131-4 [DOI] 10.1021/cb1002575. [PMID] 21043485.
2011
Observing selected domains in multi-domain proteins via sortase-mediated ligation and NMR spectroscopy.
Journal of biomolecular NMR. 49(1):3-7 [DOI] 10.1007/s10858-010-9464-2. [PMID] 21188472.
2011
The REV-ERBs and RORs: molecular links between circadian rhythms and lipid homeostasis.
Future medicinal chemistry. 3(5):623-38 [DOI] 10.4155/fmc.11.9. [PMID] 21526899.
2010
Characterization of the core mammalian clock component, NPAS2, as a REV-ERBalpha/RORalpha target gene.
The Journal of biological chemistry. 285(46):35386-92 [DOI] 10.1074/jbc.M110.129288. [PMID] 20817722.
2009
Structural and motional contributions of the Bacillus subtilis ClpC N-domain to adaptor protein interactions.
Journal of molecular biology. 387(3):639-52 [DOI] 10.1016/j.jmb.2009.01.046. [PMID] 19361434.
2008
Implications of the binding of tamoxifen to the coactivator recognition site of the estrogen receptor.
Endocrine-related cancer. 15(4):851-70 [DOI] 10.1677/ERC-07-0281. [PMID] 18755852.
2008
Insights into the nature of DNA binding of AbrB-like transcription factors.
Structure (London, England : 1993). 16(11):1702-13 [DOI] 10.1016/j.str.2008.08.014. [PMID] 19000822.
2007
Classification of response regulators based on their surface properties.
Methods in enzymology. 422:141-69 [PMID] 17628138.
2007
NMR assignment of the N-terminal repeat domain of Bacillus subtilis ClpC.
Biomolecular NMR assignments. 1(2):163-5 [DOI] 10.1007/s12104-007-9046-8. [PMID] 19636855.
2006
Structure, binding interface and hydrophobic transitions of Ca2+-loaded calbindin-D(28K).
Nature structural & molecular biology. 13(7):641-7 [PMID] 16799559.
2005
(4,2)D Projection–reconstruction experiments for protein backbone assignment: application to human carbonic anhydrase II and calbindin D(28K).
Journal of the American Chemical Society. 127(24):8785-95 [PMID] 15954785.
2005
Solution structure and dynamics of LuxU from Vibrio harveyi, a phosphotransferase protein involved in bacterial quorum sensing.
Journal of molecular biology. 347(2):297-307 [PMID] 15740742.
2005
Structural analysis of divalent metals binding to the Bacillus subtilis response regulator Spo0F: the possibility for in vitro metalloregulation in the initiation of sporulation.
Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine. 18(5):449-66 [PMID] 16333746.
2003
Calbindin D28K interacts with Ran-binding protein M: identification of interacting domains by NMR spectroscopy.
Biochemical and biophysical research communications. 303(4):1186-92 [PMID] 12684061.
2003
Sub-classification of response regulators using the surface characteristics of their receiver domains.
FEBS letters. 554(3):231-6 [PMID] 14623071.
2002
Alternative splicing of a beta4 subunit proline-rich motif regulates voltage-dependent gating and toxin block of Cav2.1 Ca2+ channels.
The Journal of neuroscience : the official journal of the Society for Neuroscience. 22(21):9331-9 [PMID] 12417658.
A structural mechanism for directing inverse agonism of PPARγ
. [DOI] 10.1101/245852.
Assessment of NR4A Ligands that Directly Bind and Modulate the Orphan Nuclear Receptor Nurr1
. [DOI] 10.1101/2020.05.22.109017.
Cooperative Cobinding of Synthetic and Natural Ligands to the Nuclear Receptor PPARγ
. [DOI] 10.1101/252817.
Defining a canonical ligand-binding pocket in the orphan nuclear receptor Nurr1
. [DOI] 10.1101/278440.
Molecular basis of ligand-dependent Nurr1-RXRα activation
. [DOI] 10.1101/2022.11.08.515219.
Quantitative Structural Assessment of Graded Receptor Agonism
. [DOI] 10.1101/617100.
Structural basis for heme-dependent NCoR binding to the transcriptional repressor REV-ERBβ
. [DOI] 10.1101/2020.05.05.079277.
Structural basis of altered potency and efficacy displayed by a major in vivo metabolite of the anti-diabetic PPARγ drug pioglitazone
. [DOI] 10.1101/351346.
Structural basis of interdomain communication in PPARγ
. [DOI] 10.1101/2022.07.13.499031.
Structural Mechanism Underlying Ligand Binding and Activation of PPARγ
. [DOI] 10.1101/2020.09.22.298109.

Grants

Apr 2022 ACTIVE
Molecular basis of activation of the orphan nuclear receptor Nurr1
Role: Principal Investigator
Funding: NATL INST OF HLTH NIA
Apr 2022 ACTIVE
Mechanistic studies of corepressor-mediated PPAR? transcriptional repression
Role: Principal Investigator
Funding: NATL INST OF HLTH NIDDK
Apr 2022 ACTIVE
Identification of REV-ERB inverse agonists for cancer immunotherapy
Role: Co-Investigator
Funding: NATL INST OF HLTH NCI
Apr 2022 ACTIVE
Elucidating the molecular mechanisms underlying ligand-dependent REV-ERB activity in Th17 cells
Role: Other
Funding: NATL INST OF HLTH NIDDK
Apr 2022 – Aug 2022
HIV Interactions in Viral Evolution
Role: Co-Investigator
Funding: SEATTLE CHILDRENS HOSPITAL via NATL INST OF HLTH NIAID
Apr 2022 – May 2022
Identification of Chemical Probes for the Orphan Nuclear Receptor NR2F6
Role: Co-Investigator
Funding: NATL INST OF HLTH NCI

Education

Ph.D. in Biochemistry
2005 · North Carolina State University
Bachelor's of Science in Chemistry
2000 · Purdue University

Contact Details

Phones:
Business:
(561) 228-2298
Emails:
Business:
dkojetin@ufl.edu
Addresses:
Business Mailing:
130 SCRIPPS WAY RM A216 # 2A1
JUPITER FL 33458