Journal of Molecular Endocrinology 25th anniversary special issue

    1. Ronald M Evans
    1. Investigator, Howard Hughes Medical Institute and Professor, Salk Institute for Biological Studies, La Jolla, CA, USA
    1. Correspondence should be addressed to R M Evans; Email: evans{at}; or cbrondos{at}

    Nuclear receptors (NRs) comprise a large family of signal dependent transcription factors that respond to a diverse range of fat soluble ligands including steroids, vitamins A and D, long chain fatty acids, bile acids, thyroid hormone and xenobiotic toxins. Through their cognate receptors, nuclear-active hormones orchestrate a multiplicity of biological functions from embryonic development to endocrine physiology, pathology, and therapeutics. Since the cloning of the human glucocorticoid receptor (hGR) in 1985 and the estrogen receptor (ER) in 1986 this family has grown to include 48 unique receptors integrally linked to the evolution of the entire animal kingdom. Intense research efforts have been dedicated to understanding the molecular mechanism of nuclear hormone signaling and how receptor interactions with the genome influence basic biology. At a structural level, NR-mediated transcriptional activation is a complex, multistep process orchestrated primarily by the concerted actions of a DNA binding domain (DBD) and a ligand binding domain (LBD) incorporating coregulator binding sites. While initial structural studies on isolated domains provided a fundamental understanding of the discrete functions of these domains, a fully integrated picture on how NRs are dynamically regulated to enact a coordinated gene transcription response was lacking. Newly emerging crystal structures, reviewed by Fraydoon Rastinejad, are now shedding light on the quaternary arrangement of NR protein complexes, with direct implications for drug discovery and design (Rastinejad et al. 2013). Concurrently, tremendous advances in structural studies of coregulator proteins, reviewed by John Schwabe, are revealing how NRs orchestrate protein …

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