Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor. Cell 2018 Jan 11;172(1-2):55-67.e15
Date
01/09/2018Pubmed ID
29307491Pubmed Central ID
PMC5802374DOI
10.1016/j.cell.2017.12.011Scopus ID
2-s2.0-85039900111 (requires institutional sign-in at Scopus site) 291 CitationsAbstract
The κ-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 κ-opioid receptor therapeutics.
Author List
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 BLAuthors
John McCorvy PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinPhilip Mosier PhD Assistant Professor in the School of Pharmacy Administration department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnalgesicsAnimals
Binding Sites
HEK293 Cells
Humans
Molecular Docking Simulation
Molecular Dynamics Simulation
Morphinans
Protein Binding
Protein Stability
Receptors, Opioid, kappa
Sf9 Cells
Spodoptera