We study ligand-dependent transcription factors, with a current focus on the human basic Helix Loop Helix-PAS (bHLH-PAS) protein family. Within this family, class I and class II members heterodimerize to generate functional transcription factors. Class I members include three hypoxia-inducible factors (HIF-1α, HIF-2α and HIF-3α), the aryl hydrocarbon receptor (AHR), the aryl hydrocarbon receptor repressor (AHRR), four neuronal PAS proteins (NPAS1, NPAS2, NPAS3, NPAS4), two single-minded proteins (SIM1, SIM2), and the clock circadian regulator (CLOCK). Class II members include the aryl hydrocarbon receptor nuclear translocator (ARNT, also called HIF-1β), ARNT2, brain and muscle ARNT-like protein 1 (BMAL1, also called ARNTL), and BMAL2 (ARNTL2).
A unifying feature of this family is their reliance on PAS domains, whose name derives from the proteins Period, ARNT, and SIM. PAS domains evolved for detecting signals in bacteria, archaea and eukaryotic organisms, but in most cases the signals for bHLH-PAS proteins remain unknown. Further unifying members of this family are their common polypeptide arrangements, where tandem PAS domains (known as PAS-A and PAS-B) lie adjacent to a conserved bHLH DNA-binding domain, and are followed by a variable transactivation domain.
We have recently reported a series of crystal structures showing the bHLH-PAS proteins comprise a distinct family of ligand-binding transcription factors in mammals. We observed that each of their PAS domains harbors a ligand-binding pocket. In bHLH-PAS proteins, the PAS domains present an empty pocket at their center. The volumes and the amino-acids lining these pockets are unique for each member of the family, suggesting distinct endogenous ligands should exist. The functional heterodimers formed in this family bring together four distinct ligand-binding pockets, twice the number in nuclear receptor heterodimers.
Our research program emphasizes ligand discovery for this family, taking into account their individual PAS-A and PAS-B domains. We are biochemically preparing each individual PAS domain in multi-milligram amounts, and relying on innovative biochemical screening strategies that identify chemical ligands. To generate a coherent understanding of ligand-dependent actions in this family, we are attempting to link the discovery of chemical ligands to the genomic signatures of each family member. Furthermore, we are interested in addressing mechanistic questions about ligand-modulation in this family. For this purpose,we are applying structural analyses to study the stereochemical basis for ligand binding and ligand actions through induced conformational changes in these proteins.
Professor, University of Oxford, Nuffield Department of Medicine
- Professor of Biochemistry and Structural Biology
- Wellcome Trust Senior Investigator
- Member of Congregation
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