A compilation of cryo-EM images has been presented. Monochromatic images show 2D projections from multiple angles of the imaging scaffold connected to a specific protein, while a colored image reveals the 3D construction generated from these 2D projections. Credit is due to Roger Castells-Graells of UCLA.
Breakthroughs in cryo-electron microscopy (cryo-EM) have important implications for research focused on developing potential treatments for cancer.
Conventionally, cryo-electron microscopy has allowed scientists to view biological molecules’ atomic structures in high definition. However, the technique has thus far been less effective in imaging smaller molecules. A research team led by UCLA biochemists has formulated a method to stabilize small protein molecules during imaging, enhancing cryo-EM’s ability to produce more detailed images of such molecules. This development holds particular importance as research involving small and medium-sized protein molecules may lead to new pharmaceuticals for cancer and other ailments.
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Notable Enhancements to Award-Winning Imaging Technique
In 2017, the Nobel Prize in Chemistry was conferred upon researchers for the innovation of cryo-electron microscopy, which has revolutionized the high-resolution imaging of large biological molecules. Nevertheless, the technique had its limitations: specifically, its inability to effectively image small molecules.
Biochemists from the University of California, Los Angeles, in collaboration with pharmaceutical industry researchers, have devised a method allowing cryo-EM to capture high-quality images of smaller proteins as well. The team engineered a cube-shaped, 20-nanometer protein structure, termed a scaffold, featuring rigid, tripod-like extensions that secure the smaller proteins in position.
During image processing, this scaffold can be digitally eliminated, rendering a composite 3D image solely of the small protein under examination.
Research into small and medium-sized proteins holds great promise for the development of new pharmaceuticals that could address some of humanity’s most challenging diseases. Tested on a protein currently under study for its potential utility in cancer treatment, this development can be adapted for nearly any small protein. The expansion of cryo-EM’s imaging scope is expected to facilitate the identification of precise protein sites for therapeutic targeting.
Mechanism of Cryo-EM
In the cryo-EM process, a cryo-electron microscope projects a stream of electrons through a frozen material sample, creating an image of the thousands of molecules within the sample, such as proteins. These molecules are captured in their natural state, resulting in thousands of 2D images from varying perspectives. Computer algorithms then assimilate these images to create a singular high-definition 3D image of a molecule.
However, the diminutive size of the smallest protein molecules complicates the determination of their orientations within the images, culminating in lower-resolution outcomes.
Previous attempts to resolve this issue involved attaching small molecules to larger scaffolds, but these endeavors were unsuccessful due to varying orientations of the smaller molecules, leading to unclear images.
According to Todd Yeates, UCLA distinguished professor emeritus of biochemistry and the paper’s corresponding author, the new tripod-shaped scaffold successfully held the proteins in a fixed position, thereby attaining the sought-after high-resolution images.
Applications in Pharmaceutical Research
The scaffold was tested by endeavoring to image a protein called KRAS, which plays a significant role in approximately 25% of human cancers. Its importance in drug development stems from the possibility of neutralizing its cancer-causing properties by targeting specific protein locations.
Using the new cryo-EM technique along with the developed scaffold, the UCLA team successfully observed KRAS in connection with a drug molecule currently under investigation for lung cancer treatment. The study confirmed that the new scaffold-enhanced cryo-EM method could clarify how drug molecules interact with cellular proteins like KRAS, thereby assisting in the formulation of more effective pharmaceuticals.
The recent research paper was published in the Proceedings of the National Academy of Science (PNAS) and was supported by the National Institutes of Health and the Department of Energy, in collaboration with scientists from Astra-Zeneca and Gandeeva Therapeutics.
UCLA has initiated a patent filing for the innovative technology. Todd Yeates, Roger Castells-Graells, and their colleagues have founded a new enterprise, AvimerBio, to commercialize new applications of these methodologies, partnering with major pharmaceutical corporations.
Frequently Asked Questions (FAQs) about cryo-EM technology advancements
What is the main advancement in cryo-EM technology discussed in the article?
The article focuses on a significant breakthrough led by UCLA biochemists in cryo-electron microscopy (cryo-EM). The team developed a method to stabilize small protein molecules during imaging. This allows cryo-EM to produce high-resolution images of these smaller molecules, which was a limitation in the past.
Why is this advancement in cryo-EM important?
The advancement is crucial because it extends the applicability of cryo-EM to include small and medium-sized protein molecules. These molecules are of significant interest in the research and development of new drugs for diseases like cancer.
Who was responsible for this development?
The research and development were spearheaded by a team of biochemists from the University of California, Los Angeles (UCLA), in collaboration with scientists from the pharmaceutical industry.
How does the new method work?
The team engineered a cube-shaped, 20-nanometer protein structure called a “scaffold,” which has rigid, tripod-like extensions. These extensions hold smaller protein molecules in place during imaging, thereby enabling high-resolution images.
What applications does this breakthrough have in pharmaceutical research?
The advancement holds great promise for the development of new pharmaceuticals that could address some of humanity’s most challenging diseases. It allows researchers to better understand the structure of small proteins, which are often the target for new drugs.
Has the research been published?
Yes, the research has been published in the Proceedings of the National Academy of Science (PNAS).
Who supported the research?
The research was supported by the National Institutes of Health and the Department of Energy. It was also a collaboration with scientists from Astra-Zeneca and Gandeeva Therapeutics.
Is there any commercialization plan for this new technology?
Yes, UCLA has initiated a patent filing for the new technology. Additionally, the researchers have founded a new company, AvimerBio, to develop commercial applications in collaboration with major pharmaceutical corporations.
More about cryo-EM technology advancements
- Proceedings of the National Academy of Sciences (PNAS) Publication
- UCLA Department of Biochemistry
- National Institutes of Health (NIH)
- Department of Energy
- AstraZeneca
- Gandeeva Therapeutics (Note: Placeholder as the article did not provide a specific link)
- Cryo-Electron Microscopy Overview
- Nobel Prize in Chemistry
