The mammalian orphan nuclear receptors: orphans as cellular guardians

In classical endocrinology, receptors are molecules that bind a hormone or a ligand to transduce signal within a target cell. Later, however, many intracellular receptors have been discovered in mammals, which have not been shown to bind endogenous ligands and are now are referred as "orphan receptors." The orphan receptors share high degree of structural and functional homology with the classical nuclear receptors (NRs) and are now part of the NR superfamily and therefore referred as orphan nuclear receptors (ONRs). Interestingly, however, ONR members are not evolutionarily or functionally linked and they form a highly diverse group within the NR superfamily. In mammals, ONRs exhibit great functional diversity and majority of them are expressed in a tissue-specific fashion. In the past one decade, functional studies have revealed that they are mediators of multitude of crucial metabolic, developmental, reproductive, and immunological functions in mammals. Emerging studies also indicate the role of ONRs in the onset of several complex human diseases and hence they may be potential candidates for therapeutic drug targeting in the future.     

Receptor-selective coactivators as tools to define the biology of specific receptor-coactivator pairs

In the absence of specific high-affinity agonists and antagonists, it has been difficult to define the target genes and biological responses attributable to many of the orphan nuclear receptors (ONRs). Indeed, it appears that many members of this receptor superfamily are not regulated by classical small molecules but rather their activity is controlled by interacting cofactors. Motivated by this finding, we have developed an approach to genetically isolate specific receptor-cofactor pairs in cells, allowing us to define the biological responses attributable to each complex. This is accomplished by using combinatorial peptide phage display to engineer the receptor interacting domain of each cofactor such that it interacts selectively with one nuclear receptor. In this study, we describe the customization of PGC-1alpha and its use to study the biology of the estrogen-related receptor alpha (ERRalpha) in cultured liver cells.     

Digging deep into the pockets of orphan nuclear receptors: insights from structural studies

Nuclear receptors comprise a large family of proteins that shares a common structure and mechanism of action. Members of this family, first cloned 20 years ago, are regulated by small lipophilic signaling molecules such as steroid hormones, retinoids and thyroid hormone. More recently, the characterization of proteins that resemble nuclear receptors (referred to as orphan receptors) has resulted in the determination of novel signaling pathways. However, many orphan-receptor ligands remain unidentified, and recent structural studies of the binding domains for orphan-receptor ligands suggest that not all of these receptors use ligand binding in a classical way. Notably, it is now evident that some orphan receptors lack the capacity for ligand binding, which suggests that they are regulated by alternative, ligand-independent mechanisms.