X-Ray Technique Obtains Protein Structures From Smallest-Ever Crystals

Growing crystals big enough to obtain a protein structure by X-ray crystallography can take years, as practitioners of the art know all too well. This is especially true of G protein-coupled receptors (GPCRs), which are targets for as many as 30% of prescription drugs. Such waits may now become a thing of the past, thanks to a team led by Vadim Cherezov of Scripps Research Institute California. The researchers obtained a high-resolution structure of a GPCR—the serotonin receptor—from crystals as tiny as 5 μm across (Science 2013, DOI: 10.1126/science.1244142). The key to the Scripps team’s success is a new sample injection system. It streams many tiny crystals, embedded in a viscous gel that mimics a cell membrane, into the path of an X-ray free-electron laser beam. The X-ray source doles out radiation in 50-femtosecond bursts to minimize crystal damage. The new serotonin receptor structure is nearly identical to established structures, but it has differences in some salt bridges and side-chain conformations. The structure was obtained at room temperature rather than the typical cryogenic temperatures, Cherezov says, so it may more accurately represent the GPCR’s natural state. Cherezov’s collaborators at Arizona State University have filed a patent application on the injection system.