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Elucidating the structural basis for differing enzyme inhibitor potency by cryo-EM.

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Structural differences in imidazoleglycerol-phosphate dehydratase (IGPD) between yeast and plants were revealed using electron microscopy. A key loop in yeast IGPD may explain why inhibitors are more potent against this enzyme.

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Area of Science:

  • Biochemistry and Structural Biology
  • Enzyme Function and Inhibition
  • Drug Discovery and Development

Background:

  • Histidine biosynthesis is crucial for plants and microbes, making imidazoleglycerol-phosphate dehydratase (IGPD) a target for herbicides and antibacterials.
  • While Arabidopsis thaliana IGPD (At_IGPD) has been structurally analyzed, Saccharomyces cerevisiae IGPD (Sc_IGPD) remains challenging for crystallography.
  • A lead inhibitor (C348) shows higher potency against Sc_IGPD than At_IGPD, but the structural basis is unknown.

Purpose of the Study:

  • To investigate structural differences between At_IGPD and Sc_IGPD using single-particle electron microscopy (EM).
  • To elucidate the molecular basis for the differential inhibitor potency observed between the two IGPD homologs.

Main Methods:

  • Single-particle electron microscopy (EM) was employed to determine the structures of At_IGPD and Sc_IGPD.
  • High-resolution EM maps (∼3 Å) allowed for de novo protein structure determination and identification of inhibitor binding sites.
  • The inhibitor binding site was validated using the existing crystal structure of the At_IGPD/C348 complex.

Main Results:

  • EM analysis revealed a 24-amino acid insertion in Sc_IGPD, forming an extended surface loop near the active site.
  • This loop in Sc_IGPD interacts with the substrate/inhibitor binding loop, potentially influencing inhibitor potency.
  • The determined structures confirmed the inhibitor binding site and provided a structural basis for observed potency differences.

Conclusions:

  • The study provides novel structural insights into the IGPD enzyme family.
  • An extended loop in Sc_IGPD is identified as a key structural feature potentially responsible for enhanced inhibitor potency.
  • Single-particle EM is demonstrated as a powerful technique for studying enzyme structures and inhibitor binding, especially for intractable targets.