Abstract
Transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel, can be directly activated by oxidants through cysteine modification. However, the patterns of cysteine modification are unclear. Structural analysis showed that the free sulfhydryl groups of residue pairs C387 and C391 were potentially oxidized to form a disulfide bond, which is expected to be closely related to the redox sensing of TRPV1. To investigate if and how the redox states of C387 and C391 activate TRPV1, homology modeling and accelerated molecular dynamic simulations were performed. The simulation revealed the conformational transfer during the opening or closing of the channel. The formation of a disulfide bond between C387 and C391 leads to the motion of pre-S1, which further propagates conformational change to TRP, S6, and the pore helix from near to far. Residues D389, K426, E685-Q691, T642, and T671 contribute to the hydrogen bond transfer and play essential roles in the opening of the channel. The reduced TRPV1 was inactivated mainly by stabilizing the closed conformation. Our study elucidated the redox state of C387-C391 mediated long-range allostery of TRPV1, which provided new insights into the activation mechanism of TRPV1 and is crucial for making significant advances in the treatment of human diseases.