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  11. Combining Microed And Native Mass Spectrometry For Structural Discovery Of Enzyme-small Molecule Complexes

Combining MicroED and native mass spectrometry for structural discovery of enzyme-small molecule complexes

Niko W Vlahakis1,2,3, Cameron W Flowers1,2,3, Mengting Liu4

  • 1Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095.

Proceedings of the National Academy of Sciences of the United States of America
|July 28, 2025

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View abstract on PubMed

Summary
This summary is machine-generated.

We developed electron diffraction with native mass spectrometry (ED-MS) to rapidly discover small molecule-protein complexes. This method accelerates structure-based drug discovery by analyzing protein-ligand interactions from crude samples.

Area of Science:

  • Structural Biology
  • Biochemistry
Keywords:
MicroEDcryoEMenzymeligand

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  • Drug Discovery

    • Background:

    • Accelerating the discovery of small molecule-protein complexes is crucial for drug development.
    • Current methods for structure determination can be time-consuming and require purified samples.

    Purpose of the Study:

    • To develop and validate a novel method, electron diffraction with native mass spectrometry (ED-MS), for rapid identification and structural characterization of small molecule-protein complexes.
    • To demonstrate the utility of ED-MS in discovering natural product ligands and screening small molecule binders.

    Main Methods:

    • Utilized fast, low-dose, event-based electron counting microcrystal electron diffraction (MicroED) data collection.
    • Integrated MicroED with native mass spectrometry (MS).
    • Applied ED-MS to crystal slurries soaked with known inhibitors, crude biosynthetic reactions, and printed ligand libraries.

    Main Results:

    • Successfully resolved the structures of E-64 and its analogs bound to papain.
    • Identified preferred natural product binding to papain and detected complexes from crude biosynthetic reactions without purification.
    • Determined the binding of avibactam to CTX-M-14 β-lactamase, including in a mixture of compounds.

    Conclusions:

    • ED-MS is a powerful technique for accelerating the discovery of small molecule-protein complexes.
    • The method enables structure-based screening of ligands against macromolecular targets using crude samples.
    • ED-MS shows significant promise for advancing drug discovery efforts.
    mass spectrometry