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Subtype-specific modulation of estrogen receptor-coactivator interaction by phosphorylation.
ACS Chem. Biol. 10, 475-484 (2015)
The estrogen receptor (ER) is the number one target for the treatment of endocrine responsive breast cancer and remains a highly attractive target for new drug development. Despite considerable efforts to understand the role of ER post-translational modifications (PTMs), the complexity of these modifications and their impact, at the molecular level, are poorly understood. Using a chemical biology approach, fundamentally rooted in an efficient protein semisynthesis of tyrosine phosphorylated ER constructs, the complex role of the ER tyrosine phosphorylation is addressed here for the first time on a molecular level. The semisynthetic approach allows for the site-specific introduction of PTMs as well as biophysical probes. A combination of biophysical techniques, including NMR, with molecular dynamics studies reveals the role of the phosphorylation of the clinically relevant tyrosine 537 (Y537) in ERα and the analogous tyrosine (Y488) in ERβ. Phosphorylation has important effects on the dynamics of the ER Helix 12, which is centrally involved in receptor activity regulation, and on its interplay with ligand and cofactor binding, but with differential regulatory effects of the analogous PTMs on the two ER subtypes. Combined, the results bring forward a novel molecular model of a phosphorylation-induced subtype specific ER modulatory mechanism, alternative to the widely accepted ligand-induced activation mechanism.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Ligand-binding Domain; Breast-cancer; Nuclear Receptor; Tyrosine 537; Helix 12; Crystal-structure; Nmr-spectroscopy; Alpha; Activation; Mutations
ISSN (print) / ISBN
1554-8929
e-ISSN
1554-8937
Journal
ACS Chemical Biology
Quellenangaben
Volume: 10,
Issue: 2,
Pages: 475-484
Publisher
American Chemical Society (ACS)
Publishing Place
Washington
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Structural Biology (STB)