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BACKGROUND: The cyclic, disulfide-containing peptide,
cyclo-Ac-[Cys-His-Pro-Gln-Gly-Pro-Pro-Cys]-NH2, binds to streptavidin with high
affinity. In streptavidin-peptide cocrystals of space group I222, cyclic peptide
monomers are bound on adjacent streptavidin tetramers related by a
crystallographic two-fold symmetry axis. We set out to determine whether the
disulfide bonds of the peptide, presented close to one another in the crystal,
could undergo disulfide interchange to form a dimer. RESULTS: When juxtaposed,
the disulfides of neighboring peptides undergo disulfide interchange, breaking
and forming covalent disulfide bonds, to produce a peptide dimer adopting the
symmetry of the crystal. This is the first example of a chemical transformation
mediated by a protein crystal lattice. The structure of the streptavidin-bound
monomer, and that of the dimer that was eventually produced from it in the
crystal, were both determined from the same single crystal studied at different
times. The two-fold symmetric peptide dimer was independently synthesized and
shown to form crystals of dimerized streptavidin. CONCLUSIONS: We have shown
that formation of a covalently linked peptide dimer can be mediated by a protein
crystal lattice. The dimer thus produced dimerizes its target, streptavidin,
suggesting that solid-state (or topochemical) reactions of this kind may be
broadly useful for the preparation of ligands that can dimerize other protein
targets.
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