5DXG

Estrogen Receptor Alpha Ligand Binding Domain Y537S Mutant in Complex with Stapled Peptide SRC2-P5

Summary for 5DXG

• Entry DOI: 10.2210/pdb5dxg/pdb
• Descriptor: Estrogen receptor, Stapled Peptide SRC2-P5, ESTRADIOL, ... (5 entities in total)
• Functional Keywords: estrogen receptor, hormone, stapled peptide, peptide mimetic, breast cancer, hormone receptor-peptide complex, hormone receptor/peptide
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 63433.20

Authors

Fanning, S.W.,Speltz, T.E.,Mayne, C.G.,Tajkhorshid, E.,Greene, G.L.,Moore, T.W. (deposition date: 2015-09-23, release date: 2016-07-27, Last modification date: 2020-02-19)

Primary citation

Speltz, T.E.,Fanning, S.W.,Mayne, C.G.,Fowler, C.,Tajkhorshid, E.,Greene, G.L.,Moore, T.W.
Stapled Peptides with gamma-Methylated Hydrocarbon Chains for the Estrogen Receptor/Coactivator Interaction.
Angew. Chem. Int. Ed. Engl., 55:4252-4255, 2016

PubMed Abstract: "Stapled" peptides are typically designed to replace two non-interacting residues with a constraining, olefinic staple. To mimic interacting leucine and isoleucine residues, we have created new amino acids that incorporate a methyl group in the γ-position of the stapling amino acid S5. We have incorporated them into a sequence derived from steroid receptor coactivator 2, which interacts with estrogen receptor α. The best peptide (IC50 =89 nm) replaces isoleucine 689 with an S-γ-methyl stapled amino acid, and has significantly higher affinity than unsubstituted peptides (390 and 760 nm). Through X-ray crystallography and molecular dynamics studies, we show that the conformation taken up by the S-γ-methyl peptide minimizes the syn-pentane interactions between the α- and γ-methyl groups.

PubMed: 26928945
DOI: 10.1002/anie.201510557

Experimental method

X-RAY DIFFRACTION (1.86 Å)