HILLSBORO, Ore. and LONDON—FEI announced recently that it and a collection of corporate and academic partners are forming the Cambridge Pharmaceutical Cryo-EM Consortium as part of a three-year agreement under which FEI will provide sample preparation and data collection services on a Titan Krios cryo-transmission electron microscope (cryo-EM) to the consortium companies for early-stage drug discovery research.
To do this, FEI has partnered with five pharmaceutical companies—Astex Pharmaceuticals, AstraZeneca, GlaxoSmithKline, Heptares Therapeutics and UCB—as well as the Medical Research Council Laboratory of Molecular Biology (MRC-LMB) and the University of Cambridge’s Nanoscience Centre.
Richard Henderson, a pioneer in the field of cryo-EM at MRC-LMB, states, “It is delightful to know that the development of cryo-EM, which many people have worked on for many years, has now reached mainstream structural biology. It is particularly satisfying that pharmaceutical companies are keen to evaluate the approach for drug development.”
The five companies involved in the consortium will share access to the technology with colleagues from the MRC-LMB and the University of Cambridge in return for expert guidance on the use of cryo-EM technology. FEI’s Titan Krios was installed at the Cambridge Nanoscience Centre in May. According to Peter Fruhstorfer, vice president and general manager of FEI Life Sciences, there will be an annual review on the success of the consortium, and a decision will be made about the future activity of the consortium after the three-year agreement is finished.
“The current configuration of the consortium contains all of the necessary aspects to test drive cryoEM successfully in the field of early drug discovery,” Fruhstorfer tells DDNews. “FEI contributes the equipment, the expertise to use the vitrification and microscope equipment and training capabilities; MRC-LMB contributes their expertise in biochemistry, sample prep, microscope application and data processing; the University of Cambridge has the high-end facility to house the microscope; and the pharmaceutical companies invest in people being trained and begin pioneering in sample processing for their early drug discovery projects.”
The pharmaceutical partners of the consortium will be able to gain higher success rates and effectiveness, says Fruhstorfer. Pharmaceutical companies can test the new technology in terms of target selection, determining ligand binding sites, studying protein-antibody interactions and other analyses, thereby speeding up their drug discovery process. “At the same time, this will be an opportunity to train their scientists in developing necessary cryo-EM skills and expertise,” says Fruhstorfer.
Cryo-EM is a form of transmission electron microscopy that has quickly become an important technique used by structural biologists today to obtain molecular-scale 3D information about protein structures. When combined with traditional methods for structure determination, such as X-ray crystallography and nuclear magnetic resonance spectroscopy, the resulting models can reveal the structure of complex, dynamic molecular assemblies down to the scale of individual atoms. The consortium’s Titan Krios will use the Relion software package, developed by Sjors Scheres at MRC-LMB, to process the image data into a visual 3D model that helps researchers see and understand the structure and function of the protein.
Sir Mark Welland, director of the Nanoscience Centre, said, “This is a great opportunity for researchers across the University to access a state-of-the-art microscope.”
“Cryo-EM 3D models allow us to see and understand the workings of protein-based molecular machines that we could not analyze before because they were too large and complex or were resistant to the preparations required for other techniques,” stated Fruhstorfer. “The technique was rapidly adopted by leading academic researchers and is now finding its way into early stage discovery and development in the pharmaceutical industry.”
The application of cryoEM technology that is most helpful for researchers in the pharmaceutical drug discovery realm, according to Fruhstorfer, is the capability to see the 3D structure of complexes which won’t crystallize. X-ray crystallography is the current method of choice for pharma researchers.
“So far, researchers have had to put aside complexes which wouldn’t crystallize, since they wouldn’t yield any result in a synchrotron beamline,” says Fruhstorfer. “CryoEM enables researchers to study proteins in their native environment, and at the same time, complement the powerful methods of X-ray crystallography and nuclear magnetic resonance spectroscopy, which have been in use in pharmaceutical research for a long time. With the resolution now nearing atomic resolution, and the size of proteins coming into the range of interest, cryoEM is a very viable and valuable method to determine the 3D structure.”