Structural insights into corepressor recognition by antagonist-bound estrogen receptors.
Direct recruitment of transcriptional corepressors to estrogen receptors (ER) is thought to contribute to the tissue-specific effects of clinically important ER antagonists. Here, we present the crystal structures of two affinity-selected peptides in complex with antagonist-bound ERalpha ligand-binding domain. Both peptides adopt helical conformations, bind along the activation function 2 coregulator interaction surface, and mimic corepressor (CoRNR) sequence motif binding. Peptide binding is weak in a wild-type context but significantly enhanced by removal of ER helix 12. This region contains a previously unrecognized CoRNR motif that is able to compete with corepressors for binding to activation function 2, thereby providing a structural explanation for the poor ability of ER to directly interact with classical corepressors. Furthermore, the ability of other sequence motifs to mimic corepressor binding raises the possibility that coregulators do not necessarily require CoRNR motifs for direct recruitment to antagonist-bound ER.
Heldring
Nina
N
Department of Biosciences and Nutrition, Karolinska Institutet, S-14157 Huddinge, Sweden. nina.heldring@biosci.ki.se
Pawson
Tanya
T
McDonnell
Donald
D
Treuter
Eckardt
E
Gustafsson
Jan-Ake
JA
Pike
Ashley C W
AC
D020816:Amino Acid Motifs; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D020836:Protein Structure, Quaternary
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D010455:Peptides