title: Structures and regulation of non-X orphan nuclear receptors: A retinoid hypothesis.
abstract: Nuclear receptors are defined as a family of ligand regulated transcription factors [1-6]. 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'.
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Ave., N.E., Grand Rapids, MI 49503, USA; Autophagy Research Center, University of Texas Southwestern Medical Center, 6000Harry Hines Blvd., Dallas, TX 75390, USA. Electronic address: Xiaoyong.Zhi@UTsouthwestern.edu.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Zhi
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Ave., N.E., Grand Rapids, MI 49503, USA.
authors.forename: X Edward
authors.initials: XE
authors.lastname: Zhou
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Ave., N.E., Grand Rapids, MI 49503, USA.
authors.forename: Karsten
authors.initials: K
authors.lastname: Melcher
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Ave., N.E., Grand Rapids, MI 49503, USA; VARI-SIMM Center, Key Laboratory of Receptor Research, Shanghai Institute of MateriaMedica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: Eric.Xu@vai.org.
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
mesh_terms: D000818:Animals; D001665:Binding Sites; D051837:COUP Transcription Factor II / Q000737:chemistry / Q000378:metabolism; D057137:DAX-1 Orphan Nuclear Receptor / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D057125:Nuclear Receptor Subfamily 2, Group C, Member 2 / Q000737:chemistry / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism; D012176:Retinoids / Q000737:chemistry / Q000378:metabolism*; D054339:Steroidogenic Factor 1 / Q000737:chemistry / Q000378:metabolism
chemical_list: D051837:COUP Transcription Factor II; D057137:DAX-1 Orphan Nuclear Receptor; C539965:NR0B1 protein, human; C403073:NR2E3 protein, human; C082631:NR5A2 protein, human; D057125:Nuclear Receptor Subfamily 2, Group C, Member 2; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D012176:Retinoids; D054339:Steroidogenic Factor 1; C099713:nuclear receptor subfamily 0, group B, member 2
keywords: Crystal structure; Gene repression; Ligand; Orphan nuclear receptor