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Structural Basis of Inhibition of ERα-Coactivator Interaction by High-Affinity N-Terminus Isoaspartic Acid Tethered Helical Peptides.

Authors :
Mingsheng Xie
Hui Zhao
Qisong Liu
Yujia Zhu
Feng Yin
Yujie Liang
Yanhong Jiang
Dongyuan Wang
Kuan Hu
Xuan Qin
Zichen Wang
Yujie Wu
Naihan Xu
Xiyang Ye
Tao Wang
Zigang Li
Source :
Journal of Medicinal Chemistry. 11/9/2017, Vol. 60 Issue 21, p8731-8740. 10p.
Publication Year :
2017

Abstract

Direct inhibition of the protein--protein interaction of ERα and its endogenous coactivators with a cell permeable stabilized peptide may offer a novel, promising strategy for combating ERα positive breast cancers. Here, we report the co-crystal structure of a helical peptide stabilized by a N-terminal unnatural cross-linked aspartic acid (TD) in complex with the ERα ligand binding domain (LBD). We designed a series of peptides and peptide 6 that showed direct and high-affinity binding to ERα with selective antiproliferative activity in ERα positive breast cancer cells. The co-crystal structure of the TD-stabilized peptide 6 in complex with ERα LBD further demonstrates that it forms an α helical conformation and directly binds at the coactivator binding site of ERα. Further studies showed that peptide 6W could potently inhibit cellular ERα's transcriptional activity. This approach demonstrates the potential of TD stabilized peptides to modulate various intracellular protein--protein interactions involved in a range of disorders. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00222623
Volume :
60
Issue :
21
Database :
Academic Search Index
Journal :
Journal of Medicinal Chemistry
Publication Type :
Academic Journal
Accession number :
126249322
Full Text :
https://doi.org/10.1021/acs.jmedchem.7b00732