 The study presented here provides new insights into the molecular mechanism of action of the TRPV4 ion channel. The authors have identified the binding site of the TRPV4 agonist 4PDD and the inhibitor HC 0670 for 7 at the base of the S1, S4 bundle, and showed that agonist binding leads to pore opening, while channel inhibition involves a to transition in the pore-forming helix S6. These structures elucidate the interaction interface between HTRPV4 and ROA, as well as residues at this interface that are involved in TRPV4 disease-causing mutations. This work sheds light on TRPV4 activation and inhibition and provides a template for the design of future therapeutics for treatment of TRPV4-related diseases. This article was authored by Kirill Dina-Destin, Irina A. Talizina, Aravind Patasati, and others.