De novo design of a protein binder against Staphylococcus enterotoxin B

Staphylococcus enterotoxin B (SEB) interacts with MHC-II molecules to overactivate immune cells and thereby to produce excessive pro-inflammatory cytokines. Disrupting the interactions between SEB and MHC-II helps eliminate the lethal threat posed by SEB. In this study, a de novo computational approach was used to design protein binders targeting SEB. The MHC-II binding domain of SEB was selected as the target, and the possible promising binding mode was broadly explored. The obtained original binder was folded into triple-helix bundles and contained 56 amino acids with molecular weight 5.9 kDa. The interface of SEB and the binder was highly hydrophobic. ProteinMPNN optimization further enlarged the hydrophobic region of the binder and improved the stability of the binder-SEB complex. In vitro study demonstrated that the optimized binder significantly inhibited the inflammatory response induced by SEB. Overall, our research demonstrated the applicability of this approach in de novo designing protein binders against SEB, and thereby providing potential therapeutics for SEB induced diseases.