Journal
MOLECULAR CELL
Volume 57, Issue 6, Pages 1047-1058Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2015.01.025
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Funding
- Komen Foundation [5PG12221410]
- Clayton Foundation Research grants
- DOD [R038318-I]
- NIH [HD8818, NIDDK59820, P41GM103832, R01GM079429, R01GM080139, K01DK084209, P30DK079638PJ4]
- NCI Cancer Center Support Grant [P30CA125123]
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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 ER alpha, 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 ER alpha monomers independently recruits one SRC-3 protein via the transactivation domain of ER alpha; 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.
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