An Effective Strategy for Stabilizing Minimal Coiled Coil Mimetics

Journal of the American Chemical Society
Michael G WuoParamjit S Arora

Abstract

Coiled coils are a major motif in proteins and orchestrate multimerization of various complexes important for biological processes. Inhibition of coiled coil-mediated interactions has significant biomedical potential. However, general approaches that afford short peptides with defined coiled coil conformation remain elusive. We evaluated several strategies to stabilize minimal helical bundles, with the dimer motif as the initial focus. A stable dimeric scaffold was realized in a synthetic sequence by replacing an interhelical ionic bond with a covalent bond. Application of this strategy to a more challenging native protein-protein interaction (PPI) suggested that an additional constraint, a disulfide bond at the internal a/d' position along with a linker at the e/e' position, is required for enhanced conformational stability. We anticipate the coiled coil stabilization methodology described herein to yield new classes of modulators for PPIs.

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Citations

Feb 10, 2016·Journal of the American Chemical Society·Anupam Bandyopadhyay, Jianmin Gao
Aug 25, 2015·Journal of the American Chemical Society·Andrew M WatkinsParamjit S Arora
Apr 29, 2016·Current Opinion in Structural Biology·Raheleh Rezaei Araghi, Amy E Keating
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Methods Mentioned

BETA
NMR
total correlation spectroscopy

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