Heating proteins to body temperature reveals new drug targets

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The general structures of TRPM4cold bound to Ca2+ and TRPM4hot bound to Ca2+Approx2+ and DVT, or Approx2+ and ATP. The structures are shown as a single-subunit surface view in cartoon, parallel to the membrane (top row) or from the intracellular side (bottom row). Credit: Nature (2024). DOI: 10.1038/s41586-024-07436-7

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The general structures of TRPM4cold bound to Ca2+ and TRPM4hot bound to Ca2+Approx2+ and DVT, or Approx2+ and ATP. The structures are shown as a single-subunit surface view in cartoon, 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 change shape when exposed to different temperatures, revealing previously unknown drug binding sites, new research shows.

The findings, published in Nature, could revolutionize large parts of biology by fundamentally changing the way protein structure is studied and used for drug design. The study was led by Juan Du, Ph.D., and Wei Lü, Ph.D. from the Van Andel Institute.

Proteins are generally examined at low temperatures to ensure their stability. However, the new study shows that certain proteins are very sensitive to temperature and change shape when viewed at body temperature.

“The methods we’ve used to study proteins require them to be cold or frozen for a long time, 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 shows that some proteins dramatically change their structure when warm, opening new possibilities for structure-guided drug development.”

Proteins are the molecular workhorses of the body. Their shape determines how they interact with other molecules to do their work. By determining the protein structure, scientists can create blueprints that guide the development of more effective drugs, just as locksmiths design keys that fit specific locks.


Proteins are usually studied at low temperatures. New findings from the laboratories of Dr. Juan Du and Dr. However, Wei Lu from the Van Andel Institute show that certain proteins, such as TRPM4, are very sensitive to temperature and change shape when viewed at body temperature. This change can reveal previously hidden drug binding sites. With thanks to 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 influences molecular function in the body, studying proteins at physiological temperature is a technological challenge. The research from the Du and Lü labs describes how they overcame these problems and provides scientists with a roadmap for doing so in their own experiments.

The study focused on a protein called TRPM4, which supports heart function and metabolism, including the release of insulin. As such, TRPM4 has been linked to stroke, heart disease and diabetes, among other causes.

To visualize TRPM4 at body temperature, the team used VAI’s powerful array of cryo-electron microscopes (cryo-EM), which allows scientists to quickly freeze proteins and compile detailed images of their structures. Instead of 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 this, they discovered that ligands – molecules that bind to proteins – interact with completely different sites on TRPM4 at body temperature than at lower temperatures.

The implications of the current research are far-reaching and reinforce the importance of studying proteins at body temperature to ensure the 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 were collected in VAI’s Cryo-EM Core and David Van Andel Cryo-Electron Microscopy Suite.

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

Magazine information:
Nature

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