Forty sites of TRP channel regulation

Transient receptor potential (TRP) channels are polymodal molecular sensors that integrate chemical, thermal, mechanical and electrical stimuli and convert them into ionic currents that regulate senses of taste, smell, vision, hearing, touch and contribute to perception of temperature and pain. TRP channels are implicated in the pathogenesis of numerous human diseases, including cancers, and represent one of the most ardently pursued drug targets. Recent advances in structural biology, particularly associated with the cryo-EM “resolution revolution”, yielded numerous TRP channel structures in complex with ligands that might have therapeutic potential. In this review, we describe the recent progress in TRP channel structural biology, focusing on the description of identified binding sites for small molecules, their relationship to membrane lipids, and interaction of TRP channels with other proteins. The characterized binding sites and interfaces create a diversity of druggable targets and provide a roadmap to aid in the design of new molecules for tuning TRP channel function in disease conditions.