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Related Experiment Videos

Allosteric inhibition through core disruption.

James R Horn1, Brian K Shoichet

  • 1Drug Discovery Program, Department of Molecular Pharmacology and Biological Chemistry, Northwestern University School of Medicine, 303 East Chicago Ave, Chicago, IL 60611-3008, USA.

Journal of Molecular Biology
|March 24, 2004
PubMed
Summary
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Two new beta-lactamase inhibitors were discovered to bind a cryptic site, creating a novel binding pocket. This binding induces conformational changes, offering new therapeutic design strategies.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Enzyme Inhibition

Background:

  • Protein inhibitors typically bind to pre-formed sites.
  • Inhibitor binding to unfolded states or disrupting protein structure is theoretically possible but lacks structural models.
  • Beta-lactamase is a key enzyme targeted in antibiotic resistance.

Purpose of the Study:

  • To investigate novel inhibitors of beta-lactamase.
  • To elucidate the structural basis of inhibition by destabilizing the enzyme.
  • To explore a theoretical model of inhibitor binding to non-native protein conformations.

Main Methods:

  • X-ray crystallography was used to determine the structures of beta-lactamase in complex with novel inhibitors.
  • Enzyme activity assays and thermal stability studies were performed.

Related Experiment Videos

  • Comparative analysis of inhibitor binding to wild-type and mutant beta-lactamase variants.

    • Main Results:

    • Two novel inhibitors were identified that destabilize beta-lactamase at high temperatures.
    • X-ray structures revealed inhibitors binding to a cryptic site formed by separating helices 11 and 12.
    • Inhibitor binding induced conformational changes transmitted to the catalytic residue Arg244, altering its conformation.
    • The binding site was located 16 Å from the active site, within the hydrophobic core.

    Conclusions:

    • The study provides the first structural evidence for inhibitors binding to a cryptic site induced by the inhibitor itself.
    • This mechanism represents a novel mode of enzyme inhibition, moving beyond traditional active site targeting.
    • The findings suggest new possibilities for designing inhibitors targeting such induced cryptic sites for therapeutic purposes.