Institute of Microbial Technology (सूक्ष्मजीव प्रौद्योगिकी संस्थान)
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  About Nuclear Receptors  
  Nuclear receptors comprise evolutionary related and ligand-regulated transcriptional factors that govern diverse physiological processes such as circadian rhythm, metabolism, development, and inflammation. Most members of this super-family have high sequence similarity and common structural organization. They have a N-terminal regulatory domain that performs ligand-independent transcriptional activation function, a central zinc-finger DNA binding domain (DBD) that directs nuclear receptors to specific motifs on the promoter of target genes, and a C-terminal ligand binding domain (LBD) that enables ligand dependent transcriptional modulation. The nature of ligand that binds to LBD has formed the basis for nuclear receptor classification. The receptors for steroid hormones, thyroid hormones, vitamin D, and retinoids have been known for decades and are grouped as ‘classical’ or endocrine nuclear receptors. While those that have no known endogenous ligands or seem to function without a ligand are categorized as ‘orphan’ nuclear receptors. The receptors which were initially recognized as orphan receptors but de-orphanized as and when their endogenous ligands were identified are now been called as ‘adopted orphan’ receptors. Interestingly, ligands for adopted orphans are metabolic intermediates and hence their function is to establish the precise metabolic state of the cell. The mode of function for endocrine nuclear receptors suggests that ligand binding signals their translocation into the nucleus where they occupy cognate response element mostly as homodimers and direct gene transcription. However, the mode of action for adopted orphan nuclear receptors is notably different from the endocrine receptors. Adopted orphans remain bound to DNA mostly as RXR heterodimers complexed with co-repressors. The ligand binding brings conformational changes and replaces co-repressors with co-activators to guide transcriptional activation. Adopted orphan and true orphan NRs are exquisite therapeutic targets because of their ability to mount an appropriate effector function by sensing the environmental cues and their least interventions by hormones.

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