Structures and regulation of non-X orphan nuclear receptors: A retinoid hypothesis

• Summarize the latest research progress on nuclear receptor structural biology.
• Dissect the structural and biochemical basis for regulation of orphan nuclear receptors.
• Hypothesize retinoid ligands for a subset of non-X orphan nuclear receptors.

Nuclear receptors are defined as a family of ligand regulated transcription factors [1], [2], [3], [4], [5] and [6]. While this definition reflects that ligand binding is a key property of nuclear receptors, it is still a heated subject of debate if all the nuclear receptors (48 human members) can bind ligands (ligands referred here to both physiological and synthetic ligands). Recent studies in nuclear receptor structure biology and pharmacology have undoubtedly increased our knowledge of nuclear receptor functions and their regulation. As a result, they point to new avenues for the discovery and development of nuclear receptor regulators, including nuclear receptor ligands. Here we review the recent literature on orphan nuclear receptor structural analysis and ligand identification, particularly on the orphan nuclear receptors that do not heterodimerize with retinoid X receptors, which we term as non-X orphan receptors. We also propose a speculative “retinoid hypothesis” for a subset of non-X orphan nuclear receptors, which we hope to help shed light on orphan nuclear receptor biology and drug discovery.This article is part of a Special Issue entitled ‘Orphan Nuclear Receptors’.