6B17

Design of a short thermally stable alpha-helix embedded in a macrocycle

Summary for 6B17

• Entry DOI: 10.2210/pdb6b17/pdb
• Descriptor: Capped-strapped peptide, 3,3'-dimethyl-1,1'-biphenyl (3 entities in total)
• Functional Keywords: de novo design, constrained peptide, de novo protein
• Biological source: synthetic construct
• Total number of polymer chains: 6
• Total formula weight: 9767.86

Authors

Wu, H.,Acharyya, A.,Wu, Y.,Liu, L.,Jo, H.,Gai, F.,DeGrado, W.F. (deposition date: 2017-09-17, release date: 2018-02-21, Last modification date: 2024-10-23)

Primary citation

Wu, H.,Acharyya, A.,Wu, Y.,Liu, L.,Jo, H.,Gai, F.,DeGrado, W.F.
Design of a Short Thermally Stable alpha-Helix Embedded in a Macrocycle.
Chembiochem, 19:902-906, 2018

PubMed Abstract: Although helices play key roles in peptide-protein and protein-protein interactions, the helical conformation is generally unstable for short peptides (10-15 residues) in aqueous solution in the absence of their binding partners. Thus, stabilizing the helical conformation of peptides can lead to increases in binding potency, specificity, and stability towards proteolytic degradation. Helices have been successfully stabilized by introducing side chain-to-side chain crosslinks within the central portion of the helix. However, this approach leaves the ends of the helix free, thus leading to fraying and exposure of the non-hydrogen-bonded amide groups to solvent. Here, we develop a "capped-strapped" peptide strategy to stabilize helices by embedding the entire length of the helix within a macrocycle, which also includes a semirigid organic template as well as end-capping interactions. We have designed a ten-residue capped-strapped helical peptide that behaves like a miniprotein, with a cooperative thermal unfolding transition and T ≈70 °C, unprecedented for helical peptides of this length. The NMR structure determination confirmed the design, and X-ray crystallography revealed a novel quaternary structure with implications for foldamer design.

PubMed: 29417711
DOI: 10.1002/cbic.201800026

Experimental method

X-RAY DIFFRACTION (1.25 Å)