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Heating proteins to body temperature reveals new drug targets

Heating proteins to body temperature reveals new drug targets
The overall structures of TRPM4cold bound to Ca2+ and TRPM4warm bound to Ca2+, Ca2+ and DVT, or Ca2+ and ATP. The structures are shown as a surface representation with one subunit in cartoon, viewed parallel to the membrane (top row) or from the intracellular side (bottom row). Credit: Nature (2024). DOI: 10.1038/s41586-024-07436-7

Some proteins shift their shape when exposed to different temperatures, revealing previously unknown binding sites for medications, new research has found.

The findings, published in Nature, could revolutionize wide swathes of biology by fundamentally changing how protein structure is studied and leveraged for drug design. The study was led by Van Andel Institute's Juan Du, Ph.D., and Wei Lü, Ph.D.

Proteins generally are investigated at to ensure their stability. However, the new study demonstrates that certain proteins are highly sensitive to temperature and change their shape when viewed at body temperature.

"For a long time, the methods we've used to study proteins require them to be cold or frozen. But in the real world, human proteins exist and function at body temperature," Du said. "Our study describes a new way to study proteins at body temperature and reveals that some proteins drastically alter their structures when warm, opening up new opportunities for structure-guided drug development."

Proteins are the molecular workhorses of the body. Their shape governs how they interact with other molecules to do their jobs. By determining , scientists can create blueprints that guide development of more effective medications, much like locksmiths designing keys to fit into specific locks.

Proteins usually are studied at low temperatures. However, new findings from the labs of Dr. Juan Du and Dr. Wei Lu at Van Andel Institute demonstrate that certain proteins, such as TRPM4, are highly sensitive to temperature and change their shape when viewed at body temperature. This change may expose previously hidden binding sites for medications. Courtesy of the Du Lab and Lü Lab, Van Andel Institute. Credit: Du Lab and Lü Lab, Van Andel Institute

Although it is well known that temperature affects molecular function in the body, studying proteins at physiological temperature has been technologically challenging. The study by the Du and Lü laboratories details how they overcame these issues and provides scientists a roadmap for doing so in their own experiments.

The study focused on a called TRPM4, which supports heart function and metabolism, including the release of insulin. As such, TRPM4 is linked to stroke, and diabetes, among other health conditions.

To visualize TRPM4 at body temperature, the team leveraged VAI's powerful suite of cryo- (cryo-EM), which allow scientists to flash freeze proteins and assemble detailed images of their structures. Rather than using a low-temperature sample, Postdoctoral Fellow Jinhong Hu, Ph.D., and colleagues in the Du and Lü laboratories heated the sample to body temperature before flash freezing it. By doing so, they found that ligands—molecules that bind to proteins—interact with totally different sites on TRPM4 at body temperature than at lower temperatures.

The implications of today's study are far-reaching and reinforce the importance of studying proteins at body temperature to ensure identification of physiologically relevant drug binding sites.

Other authors include Sung Jin Park, Ph.D., Tyler Walter, Ph.D., Ian J. Orozco, Ph.D., Garrett O'Dea and Xinyu Ye of VAI. The cryo-EM data was collected at VAI's Cryo-EM Core and David Van Andel Cryo-Electron Microscopy Suite.

More information: Jinhong Hu et al, Physiological temperature drives TRPM4 ligand recognition and gating, Nature (2024). DOI: 10.1038/s41586-024-07436-7

Journal information: Nature

Citation: Heating proteins to body temperature reveals new drug targets (2024, May 15) retrieved 25 May 2024 from
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