Fraydoon Rastinejad's Research Focus
Our laboratory is broadly interested in ligand-regulated transcription factors and their defined roles in metabolism, cancer, inflammation, and immunity. One focus area is the nuclear receptor family. We are examining how these transcription factors bind to small molecule ligands, DNA response elements, and co-regulator proteins. Central to our work is the use of protein crystallography / X-ray diffraction to directly visualize the details of these complexes in their functional states. Our most recent work with nuclear receptors has included detailed analysis of Rev-Erbα/β (Raghuram et al. NSMB 2007), PPARγ-RXRα (Chandra et al., Nature 2008), RORγt (Huh et al., Nature, 2011), and HNF-4α (Chandra et al., Nature 2013) complexes. These studies now guide the discovery and development of new ligands with therapeutic benefit for diabetes, cancer, inflammatory diseases, and autoimmune diseases.
Another area of study in the laboratory involves the mammalian bHLH-PAS family. These factors sense a variety of environmental and metabolic cues and regulate distinct gene programs accordingly. The bHLH-PAS proteins share architectural features including a conserved bHLH DNA-binding domain and tandem PAS domains. Members of this family include the hypoxia-inducible factors (HIF-1α and HIF-2α), neuronal PAS domain proteins (NPAS), aryl hydrocarbon receptor (AHR), and their common heterodimerization subunit ARNT (HIF-1β). We are finding that mammalian bHLH-PAS transcription factors can harbor multiple small-molecule binding pockets within their architectures, each of which can be exploited for functional modulation.
The HIF-1α and HIF-2α proteins are oxygen-sensitive transcription factors responsible for the progression and survival of many solid tumors in humans. These two proteins control genetic programs in angiogenesis, erythropoiesis, and metabolism required in these tumors. Our structural studies on HIF-1α/ARNT and HIF-2α/ARNT heterodimers revealed five distinct ligand-binding pockets within each complex (Wu et al. Nature 2015). We believe that a variety of small-molecule drugs may now be identified that bind to these pockets and inhibit the progression of tumors.
Fraydoon Rastinejad's Bio
Fraydoon Rastinejad, Ph.D., received B.A degrees in Mathematics and in Biochemistry & Molecular Cell Biology from Northwestern University, Evanston, Illinois, in 1987. His Ph.D. in Biophysics was earned from the University of Pennsylvania, Philadelphia, in 1992. He spent three years at Yale University training in X-ray crystallography with Professor Paul Sigler, before moving onto his first independent faculty career in 1995. Dr. Rastinejad has served as faculty at the University of Virginia School of Medicine beginning December 1995 through June 2010, where he was last appointed joint Professor of Pharmacology and Biochemistry & Molecular Genetics, and also director of the Center of Molecular Design. His current research interests, as Professor at Sanford-Burnham, involve integrating structural studies with development of small-molecule tools and cell-based characterizations of nuclear receptor pathways. In addition to the nuclear receptor arena, Dr. Rastinejad’s laboratory has elucidated a number of structures and mechanisms related to histone tail modifications and their recognition factors.