Douglas Kojetin, Ph.D.
Professor, Biochemistry
Ingram Professor of Cancer Research
Professor, Center for Structural Biology
Professor, Vanderbilt Institute of Chemical Biology
Director of Graduate Studies
Co-Leader, VICC Genome Maintenance Research Program.
Structural biology and molecular pharmacology of nuclear receptor transcription factors
Research Keywords: Nuclear receptors, transcription factors, structural biology, chemical biology, biochemistry, biophysics, pharmacology, metabolism, cancer, inflammation, neurodegeneration, circadian biology, drug discovery
Research Specialty: Structural and mechanistic studies of nuclear receptor signaling and ligand-directed therapeutic discovery
Research Description: Nuclear receptors are a superfamily of ligand-regulated transcription factors that bind endogenous metabolites—including lipids, steroid hormones, vitamins, and other cellular ligands—to translate metabolic and endocrine signals into changes in gene expression. Nuclear receptors regulate diverse physiological processes, including metabolism, inflammation, immunity, circadian rhythms, cell proliferation, and differentiation. Dysregulation of nuclear receptor function through mutation, altered expression, or aberrant signaling contributes to numerous human diseases, including cancer, metabolic disorders, cardiovascular disease, inflammatory diseases, and neurodegenerative disorders.
The Kojetin laboratory seeks to understand the molecular mechanisms that regulate nuclear receptor function and to leverage these insights for therapeutic discovery. Our studies provide a mechanistic foundation for the development of selective chemical probes and next-generation therapeutics targeting nuclear receptor signaling.
Current projects in the laboratory include:
- Structural and mechanistic studies of ligand recognition and allosteric regulation of nuclear receptors.
- Defining how ligand-regulated changes in nuclear receptor structure and dynamics and coregulator interactions regulate receptor activation and transcriptional output.
- Elucidating molecular mechanisms underlying nuclear receptor dysregulation in cancer, metabolic disease, inflammation, and neurodegeneration.
- Discovery and characterization of selective ligands and chemical probes targeting nuclear receptors, including high-throughput compound screening and collaborations with medicinal chemists.
- Development of ligand-directed pharmacological strategies to selectively modulate nuclear receptor signaling for therapeutic benefit.
We employ an interdisciplinary approach integrating structural biology, biochemistry, biophysics, chemical biology, computational biology, high-throughput compound screening, medicinal chemistry via collaborations, and molecular and cellular pharmacology to investigate fundamental mechanisms of nuclear receptor biology and enable translational therapeutic discovery.
Significance: Nuclear receptors are among the most successful drug targets in medicine, with approximately 15% of FDA-approved drugs acting on this family of proteins. Despite this success, many nuclear receptors remain poorly understood or lack chemical probles or therapeutics with the selectivity and efficacy needed to treat complex diseases. By defining the mechanistic basis of nuclear receptor regulation, our research enables the rational design of selective ligands that modulate receptor function with greater precision. These discoveries provide new opportunities for therapeutic intervention in cancer, metabolic disease, inflammatory disorders, neurodegenerative diseases, and circadian rhythm dysfunction.