title: The Drosophila orphan nuclear receptor DHR38 mediates an atypical ecdysteroid signaling pathway.
abstract: Ecdysteroid pulses trigger the major developmental transitions during the Drosophila life cycle. These hormonal responses are thought to be mediated by the ecdysteroid receptor (EcR) and its heterodimeric partner Ultraspiracle (USP). We provide evidence for a second ecdysteroid signaling pathway mediated by DHR38, the Drosophila ortholog of the mammalian NGFI-B subfamily of orphan nuclear receptors. DHR38 also heterodimerizes with USP, and this complex responds to a distinct class of ecdysteroids in a manner that is independent of EcR. This response is unusual in that it does not involve direct binding of ecdysteroids to either DHR38 or USP. X-ray crystallographic analysis of DHR38 reveals the absence of both a classic ligand binding pocket and coactivator binding site, features that seem to be common to all NGFI-B subfamily members. Taken together, these data reveal the existence of a separate structural class of nuclear receptors that is conserved from fly to humans.
authors.affiliation: Howard Hughes Medical Institute and Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Baker
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Shewchuk
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kozlova
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
authors.forename: Annie
authors.initials: A
authors.lastname: Hassell
authors.forename: Bruce
authors.initials: B
authors.lastname: Wisely
authors.forename: Justin A
authors.initials: JA
authors.lastname: Caravella
authors.forename: Millard H
authors.initials: MH
authors.lastname: Lambert
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Reinking
authors.forename: Henry
authors.initials: H
authors.lastname: Krause
authors.forename: Carl S
authors.initials: CS
authors.lastname: Thummel
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Willson
authors.forename: David J
authors.initials: DJ
authors.lastname: Mangelsdorf
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D026461:Ecdysteroids / Q000378:metabolism*; D007814:Larva / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D008675:Metamorphosis, Biological / Q000502:physiology*; D008958:Models, Molecular; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D017433:Protein Structure, Secondary / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D026461:Ecdysteroids; C095176:Hr38 protein, Drosophila; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; C066030:USP protein, Drosophila; C034808:ecdysteroid receptor