Generate “video” of changes in protein structure using new technology

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Researchers at Weill Cornell Medicine have developed a powerful new technique that generates changes in protein structure at rates of up to 50 frames per second.

To better understand how biomolecules change structurally over time, senior author Dr. Simon Schuling, Distinguished Professor of Anesthesiology Research at Weill Cornell Medicine, and colleagues developed a new approach. Researchers in this field routinely image resting proteins and other molecules fine enough to resolve the positions of individual atoms, but the resulting structural pictures and models are snapshots. Recording the dynamics of molecular structures and creating movies was a much more difficult challenge. The study’s lead author is Yining Zhang, a doctoral candidate at Weill Cornell School of Biomedical Sciences.

In the study published April 17 in the journal Nature Structural & Molecular Biology, the researchers used a relatively new measurement technique called high-speed atomic force microscopy (HS-AFM). Feel the structure. In a key innovation, scientists have discovered a way to isolate the target molecule, a single protein. This avoids the effects of protein-protein interactions and enables faster and more accurate scanning.

The researchers applied their new single-molecule HS-AFM approach to a protein called GltPh, which is a “transporter” that resides in cell membranes and guides neurotransmitter molecules into cells. Such transporters are among the favorite targets of structural biologists because of their complex and puzzling dynamics and importance in health and disease.

The researchers were able to obtain dynamic structural data of GltPh that combines unprecedented high spatial and temporal resolution and stability, allowing them to continuously record minute fluctuations in GltPh’s structure over several minutes. Ta. This unresolved phenomenon in proteins is called “wanderlast” kinetics, in which molecules have been reported to change functionally between high and low activity modes for no apparent reason. It is the meaning. This study reveals a previously unseen structural state of GltPh, in which the transporter is locked and functionally dormant, and reveals the basis of the dynamics of wanderlust.

The researchers emphasized that the new approach, which they are continually trying to optimize, is generalizable to the study of other proteins, including membrane-embedded proteins. Overall, the researchers said, the study opens new possibilities for tracking the exact structure of proteins moment by moment during their cycles of activity and dormancy.

reference: Jiang Y, Miyagi A, Wang X, Qiu B, Boudker O, Scheuring S. HS-AFM single molecule structural biology reveals the basis of transporter wandering dynamics. Nat structure mol biol. 2024.Doi: 10.1038/s41594-024-01260-3

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