Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor.

TitleStructure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor.
Publication TypeJournal Article
Year of Publication2018
AuthorsChe, T., S. Majumdar, S. A. Zaidi, P. Ondachi, J. D. McCorvy, S. Wang, P. D. Mosier, R. Uprety, E. Vardy, B. E. Krumm, G. Won Han, M-Y. Lee, E. Pardon, J. Steyaert, X-P. Huang, R. T. Strachan, A. R. Tribo, G. W. Pasternak, I. F Carroll, R. C. Stevens, V. Cherezov, V. Katritch, D. Wacker, and B. L. Roth
JournalCell
Volume172
Issue1-2
Pagination55-67.e15
Date Published2018 Jan 11
ISSN1097-4172
Abstract

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.

DOI10.1016/j.cell.2017.12.011
Alternate JournalCell
PubMed ID29307491
PubMed Central IDPMC5802374
Grant ListR01 DA027170 / DA / NIDA NIH HHS / United States
R21 DA038858 / DA / NIDA NIH HHS / United States
U19 MH082441 / MH / NIMH NIH HHS / United States
R33 DA038858 / DA / NIDA NIH HHS / United States
P30 CA016086 / CA / NCI NIH HHS / United States
R33 DA034106 / DA / NIDA NIH HHS / United States
R01 DA006241 / DA / NIDA NIH HHS / United States
R01 DA017204 / DA / NIDA NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R21 DA034106 / DA / NIDA NIH HHS / United States
P01 DA035764 / DA / NIDA NIH HHS / United States
R01 MH061887 / MH / NIMH NIH HHS / United States
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