Abstact

Peptide-modified supramolecular tweezers, a promising new class of chemical tools, were designed and employed to inhibit the interaction of the BIR domain of human survivin, a member of the chromosomal passenger complex (CPC), with the phosphorylated histone H3 N-terminal peptide. Fluorescence polarization measurements revealed a nanomolar affinity of the BIR domain for the peptide-tweezer, depending on the presence of lysine residue 121, as proven by the K121A mutant of survivin. Two crystal structures of C-terminally truncated human survivin with the peptide-tweezer molecules demonstrated that the peptide moiety binds the BIR domain as expected from the well-known published crystal structures of survivin with various peptides, but the tweezer itself, surprisingly, was bound to a putative Ca(2+) ion and the side chain of Pro26, corresponding to a previously unknown binding mode. Guided by the accessibility of survivin's lysine residues in the CPC, a number of new promising peptide tweezers was synthesized, able to connect both binding sites on the protein.