We recently determined the structure of an activated kappa opioid receptor (KOR)–agonist–nanobody complex using X-ray crystallography, demonstrating for the first time the molecular basis of KOP activation, and shedding light on kappa opioid receptor ligand selectivity and biased agonism. The mechanism by which the highly affine and non-basic natural product salvinorin A and its analogs interact with and modulate the function of the KOR has not been determined to date and is not only intriguing from a receptor–ligand interaction standpoint but is also a key to the development of potential treatments for widespread debilitating conditions such as chronic pain, itch and addiction disorders. Using the newly-determined activated KOR structure, we present a structure-guided hypothesis for the binding of salvinorin A and a series of its selected analogs, and also provide a rationale for the opioid receptor subtype selectivity and biased agonism properties of the analogs.<br/>

New insights into salvinorin A from an activated kappa opioid receptor structure

256th National Meeting (2018)

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