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- Title
Stapled Peptides with γ-Methylated Hydrocarbon Chains for the Estrogen Receptor/Coactivator Interaction.
- Authors
Speltz, Thomas E.; Fanning, Sean W.; Mayne, Christopher G.; Fowler, Colin; Tajkhorshid, Emad; Greene, Geoffrey L.; Moore, Terry W.
- 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 n m) replaces isoleucine 689 with an S-γ-methyl stapled amino acid, and has significantly higher affinity than unsubstituted peptides (390 and 760 n m). 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.
- Subjects
PEPTIDE synthesis; ISOLEUCINE; PEPTIDOMIMETICS; ESTROGEN receptors; HYDROCARBON synthesis; CONFORMATIONAL analysis; X-ray crystallography
- Publication
Angewandte Chemie International Edition, 2016, Vol 55, Issue 13, p4252
- ISSN
1433-7851
- Publication type
Article
- DOI
10.1002/anie.201510557