Biological Implications

What is the relevance of these findings?

These results provided strong clues about the likely mechanism of binding of another physiologically relevant molecule, the k-OR agonist and hallucinogenic Salvinorin A. Mutagenesis and SAR experiments suggested this molecule brings about its effects through 2-acetoxy moiety interaction with Cys315 as well as other electrophilic interactions through its thiocyanate group. The crystallization of ligand/receptor complex and testing involving SalA analogues such as 22-thiocyanatesalvinorinA will provide important evidence regarding the interactions, which drives this high affinity and selective binding event. The crystal structure of k-OR has revealed a number of shared and unique structural features which provide multiple anchoring points that allow the interaction of these opioid receptors with a wide variety of structurally different ligands, which interact with the receptor in a highly selective manner but through different mechanisms. Studies on the energetic conformations and flexibility of the ligands in the binding pocket and the different potential interactions with the pocket residues provide an important groundwork for the structure-based development of new drug agonists and antagonists, with new and more personalized therapeutic potential, which target opioid receptors.