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Meditope-Fab interaction: threading the hole.
- Source :
-
Acta crystallographica. Section F, Structural biology communications [Acta Crystallogr F Struct Biol Commun] 2017 Dec 01; Vol. 73 (Pt 12), pp. 688-694. Date of Electronic Publication: 2017 Nov 18. - Publication Year :
- 2017
-
Abstract
- Meditope, a cyclic 12-residue peptide, binds to a unique binding side between the light and heavy chains of the cetuximab Fab. In an effort to improve the affinity of the interaction, it was sought to extend the side chain of Arg8 in the meditope, a residue that is accessible from the other side of the meditope binding site, in order to increase the number of interactions. These modifications included an n-butyl and n-octyl extension as well as hydroxyl, amine and carboxyl substitutions. The atomic structures of the complexes and the binding kinetics for each modified meditope indicated that each extension threaded through the Fab `hole' and that the carboxyethylarginine substitution makes a favorable interaction with the Fab, increasing the half-life of the complex by threefold compared with the unmodified meditope. Taken together, these studies provide a basis for the design of additional modifications to enhance the overall affinity of this unique interaction.
- Subjects :
- Arginine chemistry
Binding Sites
Cetuximab chemistry
Crystallography, X-Ray
Half-Life
Hydrogen Bonding
Immunoglobulin Fab Fragments chemistry
Immunoglobulin Fab Fragments metabolism
Models, Molecular
Protein Conformation
Static Electricity
Structure-Activity Relationship
Surface Plasmon Resonance
Cetuximab metabolism
Peptides, Cyclic chemistry
Peptides, Cyclic metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2053-230X
- Volume :
- 73
- Issue :
- Pt 12
- Database :
- MEDLINE
- Journal :
- Acta crystallographica. Section F, Structural biology communications
- Publication Type :
- Academic Journal
- Accession number :
- 29199990
- Full Text :
- https://doi.org/10.1107/S2053230X17016272