New Drug Targets Unveiled through Protein Heating to Body Temperature

May 15, 2024

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By Van Andel Research Institute

New studies have revealed that certain proteins alter their form in response to varying temperature conditions, thereby uncovering novel medication binding sites.

The conclusions drawn from this research, featured in Nature, could bring about paradigm shifts in numerous biology fields. They can potentially redefine the basis on which protein structure is examined and employed for the creation of medications. Principals behind this revelation are Juan Du, Ph.D., and Wei Lü, Ph.D. from the Van Andel Institute.

Typically, proteins are examined under lower temperatures to keep their composition stable. However, the novel research indicates that some proteins are extremely temperature-sensitive, morphing their structure at body temperature.

'We have traditionally studied proteins under cold or freezing conditions. However, human proteins are mostly functioning at body temperature,' said Du. 'This fresh approach to protein study at body temperature highlights that a few proteins decidedly change their structures when warm. This opens up new avenues for structure-driven drug development.'

Proteins function as the body's molecular machinery. Their shape influences how accurately they interact with other molecules for performing their functions. Knowing the structure of proteins can help scientists chalk out blueprint for creating more efficient drugs, similar to how locksmiths design keys to fit specific locks.

It's well established that temperature influences molecular function within the body. Studying proteins at physiological temperature poses technological challenges, but Du and Lü's research details their problem-solving process and delivers a roadmap for others to replicate in their experiments.

The focal point of the research was a protein named TRPM4, which aids heart function and metabolism, including insulin release. TRPM4 has associations with health conditions such as stroke, heart disease, and diabetes.

To capture images of TRPM4 at body temperature, the team took advantage of VAI's impressive cryo-electron microscopes (cryo-EM) that flash freezes proteins to assemble detailed structure images. Jinhong Hu, Ph.D., along with Du and Lü's associates, heated the sample to body temperature ahead of flash freezing it. This enabled them to observe that molecules binding to proteins—ligands—interacted with completely different sites on TRPM4 at body temperature compared to lower temperatures.

This study's findings emphasize the need for examining proteins at body temperature to accurately identify physiologically important drug binding sites.

The other contributors to this study are Sung Jin Park, Ph.D., Tyler Walter, Ph.D., Ian J. Orozco, Ph.D., Garrett O'Dea and Xinyu Ye from VAI. The Cryo-EM Core at VAI and David Van Andel Cryo-Electron Microscopy Suite collected the Cryo-EM data.

Nature - Journal information

Via Van Andel Research Institute