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Related Experiment Videos

Conformational flexibility and protein specificity.

G C Roberts1

  • 1Department of Biochemistry, University of Leicester, UK.

Ciba Foundation Symposium
|January 1, 1991
PubMed
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Dihydrofolate reductase (DHFR) enzyme specificity is influenced by how its substrates and inhibitors bind. Conformational flexibility and alternative binding modes, even with similar energies, are key to DHFR

Area of Science:

  • Biochemistry
  • Enzymology
  • Pharmacology

Background:

  • Dihydrofolate reductase (DHFR) is a crucial enzyme and a target for important drugs like methotrexate, trimethoprim, and pyrimethamine.
  • Understanding DHFR's substrate and inhibitor binding is vital for drug development and enzyme mechanism elucidation.

Purpose of the Study:

  • To investigate the impact of protein and ligand structural changes on DHFR's conformation and dynamics.
  • To explore how conformational fluctuations and alternative binding modes influence enzyme specificity.

Main Methods:

  • Utilized Nuclear Magnetic Resonance (NMR) spectroscopy.
  • Employed site-directed mutagenesis to probe enzyme-ligand interactions.

Main Results:

Related Experiment Videos

  • Identified alternative binding modes for the substrate folate and the coenzyme NADP+.
  • Observed distinct binding orientations for folate influenced by Asp-26 ionization.
  • Demonstrated that enzyme-inhibitor complexes exhibit multiple ligand conformations with similar binding energies.

    • Conclusions:

    • Enzyme specificity is significantly affected by conformational fluctuations and alternative ligand binding modes.
    • DHFR exhibits flexibility in binding substrates, coenzymes, and inhibitors, impacting its pharmacological relevance.