Fig. 6.

PKD2 S6 conformational changes induced by F604P mutation. a Side view of superposition of S6 in the PKD2 WT (blue) and F604P (orange). The π-helix in the WT structure is indicated by an arrow. The F667 residue, located in the π-helix, and gate residue L677 are shown. b Top view of the pore lined by S6 in the PKD2 WT and F604P structures showing twisting and bending movements of distal S6 induced by the transition of π-helix to α-helix. c, d Averaged currents at +80 mV obtained under the same experimental conditions as in Fig. 3a in oocytes injected with cRNA of PKD2 WT, L677N/F676 (c) or F604P/F676 (d) double mutant. Currents were averaged from 10–13 oocytes. Ctrl, water-injected oocytes. Data are presented as mean ± SEM. Statistic significance was determined by Student’s t-test. ***P < 0.001. e Comparison between S6 in the closed (blue) and open (orange) states of PKD2, TRPV1, TRPML1 or TRPML3. The aromatic residue in the π-helix and hydrophobic gate residue were shown for each channel. PKD2 WT (PDB: 5T4D); TRPV1 apo (unliganded and closed state, PDB: 3J5P), Cap (capsaicin-bound state, PDB: 3J5R); TRPML1 apo (PDB: 5WJ5), ML-SA1 (agonist ML-SA1-bound state, PDB: 5WJ9); TRPML3 apo (PDB: 6AYE), ML-SA1 (6AYF). f Proposed mechanistic model for PKD2 activation induced by F604P mutation. The black arrows indicate proposed movements during the activation