6b73

Publication Abstract from PubMed

The kappa-opioid receptor (KOP) mediates the actions of opioids with hallucinogenic, dysphoric, and analgesic activities. The design of KOP analgesics devoid of hallucinatory and dysphoric effects has been hindered by an incomplete structural and mechanistic understanding of KOP agonist actions. Here, we provide a crystal structure of human KOP in complex with the potent epoxymorphinan opioid agonist MP1104 and an active-state-stabilizing nanobody. Comparisons between inactive- and active-state opioid receptor structures reveal substantial conformational changes in the binding pocket and intracellular and extracellular regions. Extensive structural analysis and experimental validation illuminate key residues that propagate larger-scale structural rearrangements and transducer binding that, collectively, elucidate the structural determinants of KOP pharmacology, function, and biased signaling. These molecular insights promise to accelerate the structure-guided design of safer and more effective kappa-opioid receptor therapeutics.

Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor.,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 Cell. 2018 Jan 11;172(1-2):55-67.e15. doi: 10.1016/j.cell.2017.12.011. Epub 2018 , Jan 4. PMID:29307491^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.