TRPV1 is a tetrameric ion channel primarily expressed in dorsal root ganglion (DRG) neurons, which functions in pain perception and neurogenic inflammation. TRPV1 can be activated by a range of noxious stimuli including natural products like Capsaicin actively present in chili peppers, DkTx produced by Chinese bird spiders and Resiniferatoxin (RTX) found in resin spurge. TRPV1 is also responsible for body temperature regulation through thermogenic nociception (>43 °C). We captured a series of intermediate states of TRPV1 transitioning from closed to opening when DkTx acting from pre-bound, singly-bound to double-bound, and reveal the mechanism whereby how modulation of the upper restriction by DkTx is coupled to lower gate opening. Unlike DkTx, the agonist RTX is bound in the vanilloid pocket proximal to lower gate, thereby directly inducing gating of lower restriction. we observed all possible tetrameric intermediates when vanilloids displace the endogenous lipids PI, including a single RTX, two in ortho and para positions, three and four RTX binding. Complete engagement of each RTX accordingly causes the conformational change of the ligand binding subunit. However, TRPV1 remains inactive until sufficient conformational changes take place due to fully engaged RTX in the tetrameric pockets. These findings will enhance our understanding of the function of TRP family and even other signal transducers, and provide new insights into drug development targeting TRPV1. (For details, please refer to Zhang et al., 2021.Cell).
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