Accepted Preprint (first posted online 8 October 2013)

    Understanding nuclear receptor form and function using structural biology

    1. Sepideh Khorasanizadeh
    1. F Rastinejad, Metabolic Signaling and Disease Program, Sanford-Burnham Medical Research Institute, Orlando, United States
    2. P Huang, Metabolic Signaling and Disease Program, Sanford-Burnham Medical Research Institute, Orlando, United States
    3. V Chandra, Metabolic Signaling and Disease Program, Sanford-Burnham Medical Research Institute, Orlando, United States
    4. S Khorasanizadeh, Metabolic Signaling and Disease Program, Sanford-Burnham Medical Research Institute, Orlando, United States
    1. Correspondence: Fraydoon Rastinejad, Email: frastinejad{at}sanfordburnham.org

    Abstract

    Nuclear receptors (NR) are a major transcription factor family whose members selectively bind small molecule lipophilic ligands and transduce those signals into specific changes in gene programs. For over two decades, structural biology efforts were directed exclusively on the individual ligand binding domains (LBDs) or DNA binding domains (DBDs) of these receptors. These analyses revealed the basis for both ligand and DNA binding, and also revealed receptor conformations representing both the activated and repressed states. Additionally, crystallographic studies explained how NR LBD surfaces recognize discrete portions o transcriptional coregulators. The many structural snapshots of LBDs have also guided the development of synthetic ligands with therapeutic potential. Yet, the exclusive structural focus on isolated NR domains has made it difficult to conceptualize how all the NR polypeptide segments are coordinated physically and functionally in the context of receptor quaternary architectures. Newly emerged crystal structures of the PPARγ-RXRα heterodimer and HNF-4α homodimer have now revealed the higher order organizations of these receptor complexes on DNA, as well as the complexity and uniqueness of their domain-domain interfaces. These emerging structural advances promise to better explain how signals in one domain can be allosterically transmitted to distal receptor domains, also providing much better frameworks for guiding future drug discovery efforts.

    • Received 7 August 2013
    • Revision received 26 September 2013
    • Accepted 7 October 2013
    • Accepted Preprint first posted online on 8 October 2013