Near-atomic resolution of protein structure by electron microscopy holds promise for drug discovery

NIH | MAY 16, 2015

A new study shows that it is possible to use an imaging technique called cryo-electron microscopy (cryo-EM) to view, in near-atomic detail, the architecture of a metabolic enzyme bound to a drug that blocks its activity. This advance provides a new path for solving molecular structures that may revolutionize drug development.

Drug development efforts often involve mapping contacts between small molecules and their binding sites on proteins. These mappings require the highest possible resolutions so that the shape of the protein chain can be traced and the hydrogen bonds between the protein and the small molecules it interacts with can be discerned.

In this study, the researchers were able to visualize beta-galactosidase at a resolution of 2.2 angstroms, which is comparable to the level of detail that has thus far been obtained only by using X-ray crystallography. At these high resolutions, there is enough information in the structure to reliably assist drug design and development efforts.

To determine structures by cryo-EM, protein suspensions are flash-frozen at liquid nitrogen temperatures, so the water around the protein molecules stays liquid-like. The suspensions are then imaged with electrons to obtain molecular images that are averaged together to discern a three-dimensional (3D) protein structure.

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