MicroED
MicroED is a cutting-edge technique that employs cryo-transmission electron microscopy (cryo-TEM) to obtain electron diffraction data from microcrystals. This method utilizes electrons as the incident beam, which interact more strongly with matter than X-rays, enabling structure determination from exceptionally small nanocrystals (100-300 nm). While larger crystals may exceed the electron beam's penetration capabilities, focused ion beam (FIB) milling can be employed to thin them to an appropriate thickness. By circumventing the need for large, high-quality crystals, MicroED expands the possibilities for structural analysis across a wide range of materials. Creative Bioarray offers comprehensive MicroED services, leveraging our team's extensive experience to provide high-quality data and structural solutions.
Versatile Applications Across Disciplines
MicroED is rapidly becoming an indispensable tool in diverse scientific fields. Its ability to analyze nanocrystals makes it invaluable in materials science for characterizing nanomaterials and microcrystalline compounds. In pharmaceuticals, MicroED aids in determining the structure of drug nanocrystals and polymorphs. Structural biologists leverage MicroED to solve protein structures from microcrystals that are challenging to analyze via X-ray diffraction. Furthermore, it finds application in chemical crystallography for characterizing the structure of novel chemical compounds. This powerful technique is transforming our ability to understand structures at the nanoscale.
Figure 1. MicroED workflow of small molecule structure determination (Danelius, Emma, et al. "MicroED in drug discovery." Current opinion in structural biology 79 (2023): 102549.).
Figure 2. Examples of ligand-bound protein structures solved by MicroED: a. The HCA II–AZM binding site from a 2.5 Å resolution MicroED structure. b. The3.2 Å structure of catalase solved by MicroED, showing the heme binding site. c. The MicroED structure of the CTD-SP1 fragment of HIV-1 Gag with bound maturation inhibitor bevirimat. d. The 2.5 Å MicroED structure of a protoglobin reactive carbene intermediate at the heme binding site. e. MicroED structure of the human adenosine receptor at 2.8 Å, showing the binding site of the antagonist ZMA (grey) as well as several cholesterols binding to the membrane helices (pink) (Danelius, Emma, et al. "MicroED in drug discovery." Current opinion in structural biology 79 (2023): 102549.).
Applications
MicroED technology finds significant application in a variety of fields, including:
- Drug Development: MicroED technology demonstrates significant advantages in drug development, enabling rapid crystal structure analysis of small-molecule drugs, natural products, co-crystal drugs, and more, thereby accelerating new drug development and optimizing drug design. For example, XtalPi Holdings Limited utilized MicroED to rapidly determine the polymorphic structures of Remdesivir, expediting its market launch. Additionally, MicroED is applied in studying drug-target interactions to elucidate mechanisms of drug action.
- Biomolecular Structure Determination: MicroED is widely used for resolving crystal structures of biomacromolecules such as proteins and nucleic acids. It achieves high-resolution structural analysis of microcrystals, providing critical data for biomedical research. Notable examples include the successful determination of α-synuclein and amyloid protein structures using MicroED.
- Materials Science: MicroED finds extensive applications in materials science for analyzing crystal structures of nanoscale materials. It has been employed to study materials such as Metal-Organic Frameworks (MOFs), Covalent Organic Frameworks (COFs), and Zeolites.
- Chemical Crystallography: MicroED plays a vital role in chemical crystallography by resolving crystal structures of small organic molecules. For instance, it has been used to determine the structures of natural products and vitamins.
- Co-crystal Drug Research: MicroED excels in co-crystal drug studies by enhancing the occupancy analysis of small molecules in co-crystals, significantly accelerating drug development processes.
- Integration with Cryo-Electron Microscopy: Combined with Cryo-Electron Microscopy (Cryo-EM), MicroED delivers higher-quality crystallographic data, further advancing structural biology research.
Advantages
- Minimal Sample Requirements: MicroED works with nanocrystals (even sub-micron-sized crystals) that are too small for traditional X-ray crystallography, which typically requires large, well-ordered single crystals. This is particularly valuable for studying challenging samples like natural products, pharmaceuticals, or proteins that are difficult to crystallize.
- High Resolution: It achieves atomic-level resolution (often<1.5 Å), comparable to X-ray crystallography, but with much smaller crystals. Cryo-EM, while powerful for larger complexes, often struggles to reach comparable resolution for small molecules or proteins under 100 kDa.
- Speed and Efficiency: Data collection is rapid (minutes to hours) due to the strong interaction of electrons with matter, requiring fewer crystals and shorter exposure times compared to X-ray methods. Cryo-EM workflows, in contrast, involve lengthy data acquisition and processing.
- Versatility: MicroED is applicable to a wide range of materials, including small molecules, proteins, nanoparticles, metal-organic frameworks (MOFs), and pharmaceutical co-crystals, bridging the gap between traditional crystallography and Cryo-EM.
- Cryogenic Compatibility
- Complementary to Cryo-EM
- Reduced Radiation Damage
Quotation and ordering
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