PuSH - Publikationsserver des Helmholtz Zentrums München

Tharun, I.M.* ; Nieto, L.* ; Haase, C.* ; Scheepstra, M.* ; Balk, M.* ; Möcklinghoff, S.* ; Adriaens, W.* ; Dames, S.A. ; Brunsveld, L.*

Subtype-specific modulation of estrogen receptor-coactivator interaction by phosphorylation.

ACS Chem. Biol. 10, 475-484 (2015)
Verlagsversion DOI
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
Weitere Metriken?
Zusatzinfos bearbeiten [➜Einloggen]
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter 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
Zeitschrift ACS Chemical Biology
Quellenangaben Band: 10, Heft: 2, Seiten: 475-484 Artikelnummer: , Supplement: ,
Verlag American Chemical Society (ACS)
Verlagsort Washington
Begutachtungsstatus Peer reviewed