5GTR

estrogen receptor alpha in complex with a stabilized peptide antagonist 6

Summary for 5GTR

• Entry DOI: 10.2210/pdb5gtr/pdb
• Descriptor: Estrogen receptor, ARG-IAS-ILE-0JY-DPP-ARG-0JY-0JY-GLN-NH2, ESTRADIOL (3 entities in total)
• Functional Keywords: estrogen receptor alpha, stabilized peptide, transcription
• Biological source: Homo sapiens (Human); More
• Cellular location: Isoform 1: Nucleus . Isoform 3: Nucleus. Nucleus: P03372
• Total number of polymer chains: 2
• Total formula weight: 29178.50

Authors

Xie, M.,Wang, T.,Li, Z.-G. (deposition date: 2016-08-23, release date: 2017-08-30, Last modification date: 2017-12-20)

Primary citation

Xie, M.,Zhao, H.,Liu, Q.,Zhu, Y.,Yin, F.,Liang, Y.,Jiang, Y.,Wang, D.,Hu, K.,Qin, X.,Wang, Z.,Wu, Y.,Xu, N.,Ye, X.,Wang, T.,Li, Z.
Structural Basis of Inhibition of ER alpha-Coactivator Interaction by High-Affinity N-Terminus Isoaspartic Acid Tethered Helical Peptides
J. Med. Chem., 60:8731-8740, 2017

PubMed 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 6 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.

PubMed: 29045135
DOI: 10.1021/acs.jmedchem.7b00732

Experimental method

X-RAY DIFFRACTION (2.804 Å)