Hidden Molecular "Control Switch" Uncovered Inside TRPM5 Protein

Northwestern University scientists have uncovered a hidden molecular "control switch" inside a protein that helps the body sense taste, control blood sugar and defend the gut. 

Located inside the protein TRPM5, the switch can act as both an accelerator and a brake, depending on the molecule that binds to it. Until now, scientists assumed TRPM5 could only be activated when calcium levels increased inside cells. But the new study reveals that small molecules can directly control the protein - no calcium required. 

The scientists identified one molecule that activates TRPM5 and another that binds to the exact same site yet shuts it down, revealing a dual-use control system.

Because TRPM5 is central to biological processes that connect taste, metabolism and gut health, the ability to fine-tune its activity unlocks new opportunities for therapeutic development. Potential applications include boosting insulin release to improve glucose control in diabetes, modulating taste perception to curb food cravings and regulating gut immune signaling to reduce inflammation.

The study was published today (Jan. 5) in the journal Nature Chemical Biology.

"TRPM5 is involved in metabolic disorders, including type 2 diabetes and obesity," said Northwestern's Wei Lü, who co-led the study with Juan Du. "If we can identify drugs that activate this channel, then we could promote insulin production to treat diseases that have problems with insulin secretion. Now that we have an overall architecture of what TRPM5 looks like and know how to activate and inhibit it, we have provided a basis for future drug development."

Du and Lü are professors of molecular biosciences at Northwestern's Weinberg College of Arts and Sciences, professors of pharmacology at Northwestern University Feinberg School of Medicine and members of Northwestern's Chemistry of Life Processes Institute. Zheng Ruan, a former postdoctoral fellow now an assistant professor at Thomas Jefferson University, is the study's lead author.

Acting as a signal amplifier, TRPM5 resides inside many cell types. When open, it allows sodium ions to flow through, helping cells send electrical signals that control key biological processes. In the tongue, it helps detect sweet, bitter and umami flavors. In the pancreas, it supports insulin release after meals. And in the gut, it helps sense nutrients and regulate immune defense.

In 2021, Lü and Du published a study in Nature Structural & Molecular Biology in which they revealed the first high-resolution images of TRPM5, which uncovered two areas that may serve as targets for new medications.

To better understand how this protein functions, the team used cryo-electron microscopy (cryo-EM) and electrophysiology to visualize TRPM5's inner workings in near-atomic detail. They discovered a hidden pocket that acts like a universal remote control. One type of molecule (called CBTA) fits into the pocket in a way that opens TRPM5 - like pressing the "power" button. Another type of molecule (called TPPO) fits into the same pocket differently and locks the channel closed - like pressing "mute."

The molecules look alike and bind to the same pocket but play opposite roles. This pocket has never been reported before."

Juan Du, Northwestern University

The team also found that when a molecule activates TRPM5, it becomes extra sensitive to calcium, responding to tiny changes that wouldn't typically affect it. This shows that the pocket doesn't just control the protein but can supercharge it.

The study, "A single allosteric site merges activation, modulation and inhibition in TRPM5," was supported by the National Institutes of Health, a McKnight Scholar Award, Klingenstein-Simon Scholar Award, Sloan Research Fellowship, a Pew Scholar in the Biomedical Sciences award and an American Heart Association Postdoctoral Fellowship. With its expert technical guidance and advanced infrastructure - vital for the storage, management and analysis of large cryo-electron microscopy datasets - Northwestern University Information Technology Research Computing and Data Services also supported the work.