The US National Institutes of Health (NIH) launched a $125.5-million program this past May to broaden access to the equipment and training needed for cryo-electron microscopy (cryo-EM). This massive investment in the Transformative High-Resolution Cryo-Electron Microscopy Program will support the establishment of national cryo-EM centers at Stanford University, Oregon Health & Science University and the New York Structural Biology Center (NYSBC). It is an acknowledgement of the rapid surge in demand for this powerful imaging technology, which enables researchers to obtain detailed structures of proteins that have defied analysis with X-ray crystallography. This demand is especially keen in the biopharma industry, where companies large and small are eager to view how their toughest targets interact with small molecules and biologic agents. “We are enabling projects that otherwise would not be possible,” says Claudio Ciferri, who heads Genentech's cryo-EM group. And as the power of cryo-EM grows apparent, companies are clamoring to collaborate with existing facilities—and in some cases, even establish their own imaging facilities in-house.
Medicinal chemists have long used X-ray crystallography and NMR for structure-based drug design. But whereas X-ray crystallography requires users to grapple with the finicky process of coaxing proteins to form stable crystals, cryo-EM can capture proteins above 100 kDa in size in a more natural state by rapidly freezing them into a thin layer of clear vitreous ice on the surface of an imaging grid. The sample is bombarded with electrons from a field-emission gun, and an ultra-sensitive detector captures the scattering patterns that result from electrons ricocheting off the surfaces of the trapped particles. These scattering patterns can be deciphered to obtain two-dimensional (2D) images of each particle—and since each frozen sample contains many individual protein particles in myriad orientations, their respective 2D images can then be computationally assembled into 3D reconstructions.
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