title: Topochemistry for preparing ligands that dimerize receptors.
abstract: 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.
authors.affiliation: Arris Pharmaceutical Corporation, South San Francisco, CA 94080, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Katz
authors.forename: R M
authors.initials: RM
authors.lastname: Stroud
authors.forename: N
authors.initials: N
authors.lastname: Collins
authors.forename: B
authors.initials: B
authors.lastname: Liu
authors.forename: R
authors.initials: R
authors.lastname: Arze
mesh_terms: 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*
chemical_list: D004220:Disulfides; D008024:Ligands; D018000:Receptors, Peptide; D019809:Streptavidin