3-dimensional structure and function of a TRPM ion channel

Transient receptor potential (TRP) channels belong to a family of ion channels that are activated and regulated by a wide variety of stimuli, including temperature, voltage, mechanical stress and binding of specific ligands. Consequently, TRP channels are involved in various sensations of temperature, pain, pressure, taste and vision. Current knowledge into the structure of TRP channels derives from near-atomic resolution structures of TRPV1, TRPV2 and TRPA1, which were recently determined by cryo-electron microscopy. These structures have generated a wealth of information on subunit assembly, pore formation, channel gating and regulation. Despite these remarkable breakthroughs, detailed insight into the mechanism of temperature sensation, ligand recognition and ion selection and permeation is still missing. In this study we take a hybrid structural approach to determine the 3-dimensional structure and function of the TRPM3 ion channel, using a combination of X-ray crystallography and cryo-electron microscopy. Our strategy is to divide and conquer, initially aiming for X-ray structures of the cytoplasmic regulatory domains. These structures will then be employed to facilitate the structure determination of the full-length TRPM3 channel by cryo-electron microscopy. In combination with electrophysiological recordings we will relate structure to function and pave the way for the structure-based development of novel therapeutics that can better treat TRP-related disorders.