Cancer Research with Cryo-EM

Cancer describes a large group of diseases with a diverse array of etiologies and locations, bound together by the rapid creation of abnormal cells that grow beyond physiological constraints. World Health Organization statistics show that nearly 10 million people worldwide died from cancer in 2020, with 20 million new cases diagnosed in that year. Cancer is governed by the behaviors and interactions of numerous distinct cell types, which are mediated by a vast number of protein-signaling pathways. While it is well known that mutant gene products lead to oncogenesis, the underlying mechanisms and potential protein-level therapeutic targets are largely unclear. This drives structural biologists to characterize how mutations affect protein structure and to identify how these alterations impact signaling and function.

There are numerous techniques that are used in cancer research; one of the most common is X-ray crystallography, a diffraction technique that allows researchers to study the structures of biomolecules. Crystallography inherently requires crystalline samples, which can be difficult to produce for large molecules or macromolecular complexes. With cryo-electron microscopy (cryo-EM), structural biologists can study the structures of critical proteins such as membrane receptors and other biomolecules that are difficult to crystallize. Cryo-EM allows researchers to freeze biomolecules in their native conformations and visualize protein interactions. Scientists can also use cryo-EM to capture different stages of biochemical reactions instead of just the pre-reaction and end states. With structural insights, researchers can better understand the conditions required for cancer cell growth and identify new ways to treat cancer. Learn how cryo-EM is revolutionizing cancer research in our eBook.

Membrane proteins and large macromolecular structures are challenging targets for X-ray crystallography and NMR spectroscopy. (E.g. while membrane proteins account for over 60% of drug targets, they only make up ~2% of existing crystal structures.) Generally, this means that they cannot obtain structures quickly enough to impact the drug design process. Cryo-EM techniques, meanwhile, do not require crystal growth, making them more flexible and capable of determining the structures of non-crystalline proteins. With cryo-EM, researchers can analyze the complex conformations, structures, and modified forms of proteins; multiple conformations can even be studied within a single sample. Learn more about the wide range of targets that can be studied with cryo-EM on our drug discovery page.

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