Structural guidelines for stabilization of α-helical coiled coils via PEG stapling.
RSC Chem Biol
; 3(9): 1096-1104, 2022 Aug 31.
Article
en En
| MEDLINE
| ID: mdl-36128502
ABSTRACT
Macrocyclization or stapling is one of the most well-known and generally applicable strategies for enhancing peptide/protein conformational stability and target binding affinity. However, there are limited structure- or sequence-based guidelines for the incorporation of optimal interhelical staples within coiled coils the location and length of an interhelical staple is either arbitrarily chosen or requires significant optimization. Here we explore the impact of interhelical PEG stapling on the conformational stability and proteolytic resistance of a model disulfide-bound heterodimeric coiled coil. We demonstrate that (1) interhelical PEG staples are more stabilizing when placed farther from an existing disulfide crosslink; (2) e/g' staples are more stabilizing than f/b' or b/c' staples; (3) PEG staples between different positions have different optimal staple lengths; (4) PEG stapling tolerates variation in the structure of the PEG linker and in the mode of conjugation; and (5) the guidelines developed here enable the rational design of a stabilized PEG-stapled HER-2 affibody with enhanced conformational stability and proteolytic resistance.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Tipo de estudio:
Guideline
Idioma:
En
Revista:
RSC Chem Biol
Año:
2022
Tipo del documento:
Article