Topochemistry for preparing ligands that dimerize receptors.
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.
Katz
B A
BA
Arris Pharmaceutical Corporation, South San Francisco, CA 94080, USA.
Stroud
R M
RM
Collins
N
N
Liu
B
B
Arze
R
R
D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D004220:Disulfides / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D013058:Mass Spectrometry; D008968:Molecular Conformation; D018000:Receptors, Peptide / Q000737:chemistry*; D019809:Streptavidin / Q000737:chemistry*
D004220:Disulfides; D008024:Ligands; D018000:Receptors, Peptide; D019809:Streptavidin