Structure and function of a broad-range thermal receptor in myriapods

Broad-range thermal receptor 1 (BRTNaC1), activated by heat at low extracellular pH, was recently identified in myriapods. Although the overexpression of BRTNaC1 leads to robust heat-activated current with a cation selectivity profile, the structure of this receptor and how it is gated by proton and heat remain to be investigated. Here we determine cryogenic electron microscopy structures of BRTNaC1 in the apo, proton-induced and heated states. Based on these structures, patch-clamp recordings and molecular dynamic simulations, we found that a ‘twist the wrist’ mechanism is used for proton activation of BRTNaC1, while heat induces broad conformational changes in BRTNaC1, including rotation and shift in the transmembrane helices to open this channel. Moreover, as testosterone inhibited BRTNaC1 activation, we identified four clustered residues important for such inhibition. Therefore, our study has established the structural basis for ligand and temperature gating in the BRTNaC1 ion channel. The authors reveal the structure and gating mechanisms of BRTNaC1, a myriapod ion channel sensitive to heat and acidity. They show that a proton triggers a ‘twist the wrist’ motion, heat induces broad structural changes and testosterone inhibits channel activation.