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Topochemical catalysis achieved by structure-based ligand design

B A Katz1, R T Cass, B Liu

  • 1Arris Pharmaceutical Corporation, South San Francisco, California 94080, USA.

The Journal of Biological Chemistry
|December 29, 1995
PubMed
Summary
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Researchers discovered that a streptavidin crystal lattice can catalyze the dimerization of thiol-containing peptide ligands. This protein crystal lattice-mediated catalysis is a novel finding, with the highest catalytic efficiency observed at pH 3.1.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Crystallography

Background:

  • Phage libraries yielded a cyclic peptide ligand with high affinity for streptavidin.
  • Crystal structures revealed ligand-protein interactions, guiding further design.

Purpose of the Study:

  • To design and characterize linear thiol-containing peptide ligands that bind streptavidin.
  • To investigate the catalytic dimerization of these ligands mediated by a streptavidin crystal lattice.

Main Methods:

  • Structure-based design of peptide ligands.
  • Protein crystallography to determine ligand-bound structures.
  • High-performance liquid chromatography (HPLC) and mass spectrometry to analyze ligand dimerization.
  • Kinetic studies to determine spontaneous and catalyzed disulfide formation rates across various pH levels.

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Main Results:

  • Designed linear thiol-containing ligands (FCH-PQNT-NH2 and Ac-CHPQNT-NH2) bind to streptavidin.
  • The streptavidin crystal lattice (space group I222) catalytically dimerized these ligands via disulfide bond formation.
  • Catalysis was confirmed by HPLC and mass spectrometry, with a maximal catalyzed to uncatalyzed rate ratio of 3.8 at pH 3.1.
  • Crystal structures of the dimerized ligands bound to streptavidin were determined at high resolution (1.80-1.95 Å).

Conclusions:

  • This study presents the first example of catalysis mediated by a protein crystal lattice.
  • Structure-based design enabled the development of ligands that undergo crystal-catalyzed dimerization.
  • The findings open new avenues for protein crystal lattice-based catalysis and biomolecular engineering.