Journal
CELL
Volume 172, Issue 1-2, Pages 55-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2017.12.011
Keywords
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Categories
Funding
- NIH [RO1MH61887, U19MH82441]
- NIMH Psychoactive Drug Screening Program Contract
- Michael Hooker Distinguished Chair of Pharmacology
- National Institute on Drug Abuse [DA035764, DA038858, DA0624, DA034106]
- Mayday Foundation
- Peter F. McManus Trust [DA034106]
- NIH/NCI Cancer Center support grant [P30 CA008748]
- National Cancer Institute [P30CA016086]
- Federal funds from the National Cancer Institute [ACB-12002]
- National Institute of General Medical Sciences [AGM-12006]
- DOE Office of Science [DE-AC02-06CH11357]
- NATIONAL CANCER INSTITUTE [P30CA008748, P30CA016086] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH061887, U19MH082441] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA006241, R21DA038858, R33DA034106, R21DA034106, P01DA035764, R33DA038858, R01DA017204, R01DA027170] Funding Source: NIH RePORTER
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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 k-opioid receptor therapeutics.
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