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Structure of a Biologically Active Estrogen Receptor-Coactivator Complex on DNA

2015; Elsevier BV; Volume: 57; Issue: 6 Linguagem: Inglês

10.1016/j.molcel.2015.01.025

1097-4164

Ping Yi, Zhao Wang, Qin Feng, Grigore Pintilie, Charles E. Foulds, Rainer B. Lanz, Steven J. Ludtke, Michael F. Schmid, Wah Chiu, Bert W. O’Malley,

Cancer therapeutics and mechanisms

Summary 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.