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Structures of Bacterial and Human Phosphoglycosyltransferases Bound to a Common Inhibitor Inform Selective
Beebee Yusrah Kaudeer1, Jacob M Kirsh1, Katsuhiko Mitachi2
1Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.
ACS Chemical Biology
|March 17, 2026
Summary
Researchers developed APPB, a potent inhibitor targeting MraY and DPAGT1 enzymes crucial for bacterial and cancer cell processes. Cryo-EM structures reveal inhibitor conformations, guiding the design of new antibacterial and anticancer drugs.
Area of Science:
- Biochemistry
- Structural Biology
- Drug Discovery
Background:
- Glycoconjugates are vital for biological processes, synthesized by glycan-transferring enzymes.
- MraY and DPAGT1 are orthologous phosphoglycosyltransferases essential for bacterial peptidoglycan and eukaryotic N-linked glycans, respectively.
- These enzymes are key targets for developing antibacterial and anticancer therapies.
Purpose of the Study:
- To determine the cryo-EM structures of MraY and DPAGT1 bound to the inhibitor APPB.
- To provide structural insights for designing next-generation MraY- and DPAGT1-specific inhibitors.
- To guide the development of novel antibacterial and anticancer therapeutics.
Main Methods:
- Single-particle cryo-electron microscopy (cryo-EM) at 2.9 Å resolution.
- Biochemical assays to determine inhibitor potency (IC50 values).
- Comparative structural analysis of inhibitor-bound orthologs.
Main Results:
- Cryo-EM structures revealed APPB binding to MraY and DPAGT1, showing two distinct conformations per protein.
- Inhibitor conformations correlated with local hydrogen-bonding interactions of the central amide carbonyl.
- Structural data provided specific insights into nucleoside interactions and binding site environments.
Conclusions:
- The study offers design principles for developing MraY- and DPAGT1-specific inhibitors.
- Characterizing inhibitor-bound orthologs simultaneously aids in designing selective therapeutics.
- APPB serves as a foundation for next-generation antibacterial and anticancer agents targeting these enzymes.
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