Application of Ring-Closing Metathesis to Grb2 SH3 Domain-Binding Peptides

作者：Liu Fa; Giubellino Alessio; Simister Philip C; Qian Wenjian; Giano Michael C; Feller Stephan M; Bottaro Donald P; Burke Terrence R Jr^*

来源：Biopolymers, 2011, 96(6): 780-788.

DOI：10.1002/bip.21692

• peptide macrocyclization
• ring-closing metathesis
• polyproline type II helix
• Grb2
• Sos1
• SH3 domain

Molecular processes depending on protein protein interactions can use consensus recognition sequences that possess defined secondary structures. Left-handed polyproline II (PPII) helices are a class of secondary structure commonly involved with cellular signal transduction. However, unlike a-helices, for which a substantial body of work exists regarding applications of ring-closing metathesis (RCM), there are few reports on the stabilization of PPII helices by RCM methodologies. The current study examined the effects of RCM macrocyclization on left-handed PPII helices involved with the SH3 domain-mediated binding of Sos1-Grb2. Starting with the Sos1-derived peptide "Ac-V(1-)P(2)-P(3)-P(4)-V(5)-P(6)-P(7)-R(8)-R(9)-R(10)-amide," RCM macrocyclizations were conducted using alkenyl chains of varying lengths originating from the pyrrolidine rings of the Pro(4) and Pro(7) residues. residues: The resulting macrocyclic peptide's showed increased helicity as indicated by circular dichroism and enhanced abilities to block Grb2-Sos1 interactions in cell lysate pull-down assays. The synthetic approach may be useful in RCM macrocyclizations, where maintenance of proline integrity at both ring junctures is desired.

• 出版日期2011
• 单位NIH