Figure 9.

Structural changes in the closed and open states of hTRPV4. Close-up view of the ligand binding pocket showing the key residues that form the coupling interface between the S1–S4, CD, and TRP domains in the a, closed and b, open states. Dashed lines indicate hydrogen-bonds and salt bridges. Representation of the structural changes in the selectivity filter and the intracellular gate of the pore region caused by the binding of the agonists c, 4α-PDD (yellow structure) and GSK1016790A (pink structure), or antagonists d, HC-067047 (blue structure) and GSK2798745 (cyan structure). Dashed lines indicate the distances between gating (I715 in the open state and M718 in the closed state) and selectivity filter (G679, M680) residues in opposite subunits. Upon activation by the agonist, a transition from α to π secondary structure occurs in the S6 helix, inducing a helical bend (π-hinge). The binding of the antagonist promotes a transition from π to α secondary structure, inducing the formation of an α-helix. The position of residue F707 is highlighted since it putatively stabilizes the π-helices structure through H-C···π interactions. PDB: 8FCA, 8FC8, 8T1F, and 8FC7 (resolutions are 3.41 Å, 3.47 Å, 3.49 Å and 3.30 Å, respectively) [52]. Created with PyMOL and BioRender.com.