6b73
From Proteopedia
Crystal Structure of a nanobody-stabilized active state of the kappa-opioid receptor
Structural highlights
FunctionOPRK_HUMAN G-protein coupled opioid receptor that functions as receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as receptor for various synthetic opioids and for the psychoactive diterpene salvinorin A. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling leads to the inhibition of adenylate cyclase activity. Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Plays a role in the perception of pain. Plays a role in mediating reduced physical activity upon treatment with synthetic opioids. Plays a role in the regulation of salivation in response to synthetic opioids. May play a role in arousal and regulation of autonomic and neuroendocrine functions.[1] [2] [3] [4] C562_ECOLX Electron-transport protein of unknown function. Publication Abstract from PubMedThe 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[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Escherichia coli | Homo sapiens | Lama glama | Large Structures | Carroll IF | Che T | Cherezov V | Han GW | Huang XP | Katritch V | Kormos C | Krumm BE | Lee MY | Majumdar S | McCorvy JD | Mosier PD | Pardon E | Pasternak GW | Roth BL | Stevens RC | Steyaert J | Strachan RT | Tribo AR | Uprety R | Vardy E | Wacker D | Wang S | Zaidi SA
