Structural and functional evidence for ligand-independent transcriptional activation by the estrogen-related receptor 3.
The crystal structure of the ligand binding domain (LBD) of the estrogen-related receptor 3 (ERR3) complexed with a steroid receptor coactivator-1 (SRC-1) peptide reveals a transcriptionally active conformation in absence of any ligand. The structure explains why estradiol does not bind ERRs with significant affinity. Docking of the previously reported ERR antagonists, diethylstilbestrol and 4-hydroxytamoxifen, requires structural rearrangements enlarging the ligand binding pocket that can only be accommodated with an antagonist LBD conformation. Mutant receptors in which the ligand binding cavity is filled up by bulkier side chains still interact with SRC-1 in vitro and are transcriptionally active in vivo, but are no longer efficiently inactivated by diethylstilbestrol or 4-hydroxytamoxifen. These results provide structural and functional evidence for ligand-independent transcriptional activation by ERR3.
Greschik
Holger
H
Laboratoire de Biologie et Génomique Structurales, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, B.P. 163, 67404 Illkirch, France.
Wurtz
Jean-Marie
JM
Sanglier
Sarah
S
Bourguet
William
W
van Dorsselaer
Alain
A
Moras
Dino
D
Renaud
Jean-Paul
JP
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D006224:Cricetinae; D018360:Crystallography, X-Ray; D004054:Diethylstilbestrol / Q000378:metabolism / Q000494:pharmacology; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D051548:Histone Acetyltransferases; D006801:Humans; D008024:Ligands; D008647:Mesocricetus; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D056920:Nuclear Receptor Coactivator 1; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000502:physiology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*
C490917:ESRRG protein, human; C490916:Esrrg protein, mouse; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol; D004054:Diethylstilbestrol; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1