Download MendeleyStapled Peptides with gamma-Methylated Hydrocarbon Chains for the Estrogen Receptor/Coactivator Interaction.
Speltz, T.E., Fanning, S.W., Mayne, C.G., Fowler, C., Tajkhorshid, E., Greene, G.L., Moore, T.W.(2016) Angew Chem Int Ed Engl 55: 4252-4255
- PubMed: 26928945
- DOI: https://doi.org/10.1002/anie.201510557
- Primary Citation of Related Structures:
5DX3, 5DXB, 5DXE, 5DXG, 5HYR - 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 ¦Ă-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?¦Á. The best peptide (IC50 =89?nm) replaces isoleucine?689 with an S-¦Ă-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-¦Ă-methyl peptide minimizes the syn-pentane interactions between the ¦Á- and ¦Ă-methyl groups.
Organizational Affiliation:
Department of Medicinal Chemistry and Pharmacognosy and UI Cancer Center, University of Illinois at Chicago, 833 S. Wood St., Chicago, IL, 60612, USA.
