Computational design of an epitope-specific Keap1 binding antibody using hotspot residues grafting and CDR loop swapping.

ABSTRACT: Therapeutic and diagnostic applications of monoclonal antibodies often require careful selection of binders that recognize specific epitopes on the target molecule to exert a desired modulation of biological function. Here we present a proof-of-concept application for the rational design of an epitope-specific antibody binding with the target protein Keap1, by grafting pre-defined structural interaction patterns from the native binding partner protein, Nrf2, onto geometrically matched positions of a set of antibody scaffolds. The designed antibodies bind to Keap1 and block the Keap1-Nrf2 interaction in an epitope-specific way. One resulting antibody is further optimised to achieve low-nanomolar binding affinity by in silico redesign of the CDRH3 sequences. An X-ray co-crystal structure of

SUBMITTER: Liu X 

PROVIDER: S-EPMC5269676 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature