UCLA researchers in the Department of Chemistry and Biochemistry have developed a novel approach to study protein-ligand interactions by integrating native mass spectrometry with electron diffraction.

BACKGROUND: The accurate characterization of small molecule-protein interactions is crucial for biomedical research. High-throughput structural methods, such as X-ray crystallography, provide atomic-resolution views of complexes that guide drug development. However, traditional structural methods require well-ordered crystals and struggle to capture ligand binding. Thus, there is a need for a novel approach that can deliver high-quality structures of protein-ligand complexes utilizing accessible electron microscopy tools.

INNOVATION: Researchers at UCLA have developed a method combining microcrystal electron diffraction and native mass spectrometry (ED-MS) for protein-ligand complex characterization. ED-MS enables the assignment of protein target structures obtained from crystal slurries soaked with mixtures of known inhibitors. This allows multiple ligands to be screened simultaneously, accelerating the discovery of useful information for drug discovery. ED-MS can capture non-covalent protein-ligand interactions, demonstrating its applicability for a wide range of compounds. Additionally, ED-MS can detect protein-ligand complexes from unpurified samples. Therefore, these results illustrate the utility of ED-MS for drug discovery, offering a fast and versatile alternative to traditional structural methods.

POTENTIAL APPLICATIONS:

• Drug Discovery/Development
• Natural Product Research
• Medicinal Chemistry
• High-Throughput Screening

ADVANTAGES:

• Versatility
• Works with micro/nanocrystals
• Captures complex ligand binding
• High Resolution
• Atomic-level
• Compatible with standard electron microscopy tools
• Discovery Acceleration
• Faster screening
• Reduces time/material needed

DEVELOPMENT TO DATE: Researchers have used electron diffraction to carry out structural analysis of samples on TEM grids, yielding unambiguous structures of bound ligands to target biomolecules.

Related Papers (from the inventors only):

[1] Vlahakis, N., Qu, S., Richards, L. S., Silva de Moraes, L., Cascio, D., Nelson, H. M., & Rodriguez, J. A. (2025). Fast event-based electron counting for small-molecule structure determination by MicroED. Acta Crystallographica Section C: Structural Chemistry, 81(Pt 3), 116-130. https://doi.org/10.1107/S2053229624012300

TDG Categories:

• • Chemical: Synthesis, Chemical Sensors, Chemical Processing & Manufacturing, Instrumentation & Analysis
  • Diagnostic Markers: Targets & Assays
  • Electrical: Sensors, Instrumentation
  • Life Science Research Tools: Research Methods, Microscopy and Imaging, Lab Equipment, Screening Libraries, Mass Spectrometry
  • Mechanical: Sensors, Instrumentation
  • Optics & Photonics: Microscopy, Spectroscopy

KEYWORDS: native mass spectrometry, microcrystal electron diffraction, ED-MS, structural characterization, high-throughput screening, ligand screening, protein-ligand interactions, drug-target characterization, non-covalent interactions, target screening, drug discovery, drug development, structural analysis, structural assay