Imaging the rapid binding of small molecules to proteins

What is it about?

Proteins are complex molecular machines whose structure dictates thier capability to perform important biological functions, like catalyzing chemical reactions, replicating DNA, or transporting molecules. Some pharmaceutical drugs are small molecules that bind to proteins, controlling their structure and thus efficiency at performing these functions. However, most of these drugs are developed without full knowledge of the protein structure or binding because the process of determining this information using large crystals can require years of development. We demonstrate a way around this bottleneck by solving a bound protein structure using many small micron-sized protein crystals and microfluidic mixers.

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Why is it important?

The use of many small crystals to solve the structure of a protein is a developing technique called serial crystallography. Before our manuscript, this method was only used to study protein binding dynamics at specialized facilities called X-ray Free-Electron Lasers. Our work demonstrates the technology to carry out these protein binding studies at synchrotron light sources, making these kind of studies widely available around the world. Furthermore, we show that the use of small crystals enables protein dynamics to be studied on timescales from milliseconds to seconds. This timescale is relevant for chemical binding and large-scale tertiary protein structure movements.

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