The Roth lab at the University of North Carolina Chapel Hill along with a team of investigators from Sloan Kettering, USC, RTI International, Virginia Commonwealth University and Vrije Universiteit Brussel determined the structure of the nanobody-stabilized active state of the kappa opioid receptor in complex with the novel opioid agonist MP1104. Currently the US is experiencing an opioid overdose crises of catastrophic proportions and there is tremendous need for the discovery of safe and effective medications to treat pain and associated disorders. Opioids-which target multiple opioid receptors--are both widely prescribed and effective medications although they suffer from a variety of side-effects including addiction and death due to respiratory depression upon overdose. The kappa opioid receptor has emerged as a potential target for the development of opioids with reduced addiction potential and greater safety. Here the nanobody-stabilized structure revealed key interactions essential for engendering the large-scale conformational rearrangements essential for receptor activation. Additionally, identified residues which determine kappa opioid selectivity and patterns of intracellular signaling. These insights promise to accelerate the discovery of safer and more effective opioid medications.
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Figure: Active-state structure of the kappa opioid receptor, in complex with a potent agonist, reveals key residues that propagate large-scale rearrangements and transducer binding. |
Citation: Che, T, Majumdar, S, Zaidi, SA, Ondachi, P, McCorvy, JD, Wang, S, Mosier, PD, Uprety, R, Vardy, E, Krumm, BE, Han, GW, Lee, MY, Pardon, E, Steyaert, J, Huang, XP, Strachan, RT, Tribo, AR, Pasternak, GW, Carroll, FI, Stevens, RC, Cherezov, V, Katritch, V, Wacker, D, Roth, BL., Structure of the nanobody-stabilized active state of the kappa opioid receptor, Cell 172, 55-67 (2018). DOI: 10.1016/j.cell.2017.12.011. Epub 2018 Jan 4.
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