Structure of a biologically active estrogen receptor-coactivator complex on DNA.
Estrogen receptor (ER/ESR1) is a transcription factor critical for development, reproduction, metabolism, and cancer. ER function hinges on its ability to recruit primary and secondary coactivators, yet structural information on the full-length receptor-coactivator complex to complement preexisting and sometimes controversial biochemical information is lacking. Here, we use cryoelectron microscopy (cryo-EM) to determine the quaternary structure of an active complex of DNA-bound ERα, steroid receptor coactivator 3 (SRC-3/NCOA3), and a secondary coactivator (p300/EP300). Our structural model suggests the following assembly mechanism for the complex: each of the two ligand-bound ERα monomers independently recruits one SRC-3 protein via the transactivation domain of ERα; the two SRC-3s in turn bind to different regions of one p300 protein through multiple contacts. We also present structural evidence for the location of activation function 1 (AF-1) in a full-length nuclear receptor, which supports a role for AF-1 in SRC-3 recruitment.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Clayton Foundation for Research, Houston, TX 77056, USA.
Ping
P
Yi
National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Zhao
Z
Wang
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Qin
Q
Feng
National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Grigore D
GD
Pintilie
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Charles E
CE
Foulds
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Rainer B
RB
Lanz
National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Steven J
SJ
Ludtke
National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Michael F
MF
Schmid
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: wah@bcm.edu.
Wah
W
Chiu
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: berto@bcm.edu.
Bert W
BW
O'Malley
D001665:Binding Sites; D020285:Cryoelectron Microscopy; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000737:chemistry* / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000737:chemistry* / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D056921:Nuclear Receptor Coactivator 3 / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D020218:Response Elements
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D046912:Multiprotein Complexes; D004247:DNA; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3