738 Cryo-EM and molecular dynamics of TRPV3 channel in activated state reveal structural features implicated in severe itch and hyperkeratosis

The TRPV3 channel, the dominant TRP receptor in skin, is heavily involved skin physiology. non-selective cation channel highly expressed keratinocytes and regulates epidermal barrier formation, hair follicle growth keratinocyte-mediated inflammation while also mediating cutaneous itch pain sensation. Gain of function mutations have been identified severe diseases, such as Olmsted syndrome, demonstrating a causative role keratinocyte hyperproliferation. Because this, has emerged an attractive target for treatment hyperkeratosis, cancers, disorders, itch/pain. Besides allosteric activation, activated by heat high temperature. While activation studied at functional level vitro, its structural mechanisms remain unknown. Our lab performed cryogenic electron microscopy (cryo-EM) both wild type (WT) resting states. Activated was via point mutation previously described to switch into high-temperature state. Whole-cell patch-clamp confirmed active prior cryo-EM imaging. Cryo-EM structures demonstrated remarkable similarity between heat-activated WT-resting However, difference found segment linking S6 box domains. This region contains W692G gain-of-function suggesting this feature be mechanistically related hyperkeratosis. Calorimetry experiments similar uptake capacity channels, however, molecular dynamic simulation greater random movement predisposes instability.