Topic: Structural energetics of cold sensitivity in TRPM8

Speaker: Prof. Yifan CHENG

Time: 10:20-11:30 AM, 16 March 2026

Venue: Room 110, Lynn Library

Introduction: Dr. Yifan Cheng is currently an Investigator of Howard Hughes Medical Institute and a Professor of Biochemistry and Biophysics at University of California San Francisco (UCSF). He received his Ph.D. degree in 1991 from Institute of Physics, Chinese Academy of Sciences (CAS). From 1991 to 1996, he continued his research in solid state physics and electron microscopy as a postdoctoral fellow at University of Oslo (NTNF Fellow) and Max-Planck-Institute of Metal Research (Alexander von Humboldt Fellow). In 1996, he changed his research direction to structural biology and received further training in cryo-electron microscopy (cryo-EM) from Professors Kenneth Taylor at Florida State University and Yoshinori Fujiyoshi at Kyoto University. In 1999, he joined the laboratory of Thomas Walz to setup a cryo-EM operation at Harvard Medical School. He started his independent career in 2006, joining the faculty of UCSF and has stayed there ever since. He has been an HHMI Investigator since 2015. He was elected a Fellow of the American Academy of Arts and Sciences in 2019 and a Member of the National Academy of Sciences in 2020.

Abstract: Thermosensitive TRP ion channels enable somatosensory nerve fibers to detect changes in our thermal environment over a wide physiologic range. In mammals, the menthol receptor, TRPM8, is activated by temperatures below ~26ºC and is essential for the perception of cold or chemical cooling agents. A fascinating, yet still unachieved goal is to elucidate structural mechanisms whereby TRPM8 or other thermosensitive channels are gated by changes in ambient temperature. Here, we close this gap by using cryo-EM to visualize TRPM8 channels in cellular membranes, where bona fide menthol- and cold-evoked open states are captured. By combining this structural analysis with thermodynamic measurements using hydrogendeuterium exchange mass spectrometry (HDX-MS), we are able to pinpoint the pore and TRP helices as key regions undergoing stimulus-evoked conformational dynamics that drive channel gating. Structural mechanisms associated with activation are validated by comparison of human TRPM8 with the mentholsensitive, but relatively cold-insensitive avian orthologue. We propose a free energy landscape to explain channel gating by cold or cooling agents.