Structural Characterization of Ligand-Specific Interactions in TRPV1 Channel: Gating Mechanism by Capsaicin and Capsazepine

Abstract

TRPV1 channels are polymodal receptors whose open probability is under command of several stimuli such as temperature, pH and ligands. Several studies have involved TRPV1 channels in pain sensation related to inflammatory responses and tissue damage, leading the pharmaceutical industry to the search of novel compounds able to modulate their function in order to develop novel pain relief therapies. Capsazepine is the best known TRPV1 antagonist and the residues accounting for their binding to TRPV1 channels have been identified by mutagenesis and specie-specific effects. Nevertheless, the molecular mechanism underlying capsazepine-mediated channel inhibition has not been described at molecular level to date. We performed molecular dynamics simulations of the TRPV1 channel in the open state in the absence and the presence of Capsazepine and Capsaicin in order to identify the interactions accounting of TRPV1 channel. Even when Capsazepine shares in part their binding site with the well-known TRPV1 channel agonist Capsaicin, their ligand orientation resulted to be different. We also observed a dynamic hydrogen bond network at the neighbors of the vanilloid binding pocket that differs with those observed in both the absence of ligand and in the presence of capsaicin. Our results suggest that the subtle differences at the interaction network at the capsaicin binding pocket leads to completely opposite effects at the channel activation gate.