| Literature DB >> 29307491 |
Tao Che1, Susruta Majumdar2, Saheem A Zaidi3, Pauline Ondachi4, John D McCorvy1, Sheng Wang1, Philip D Mosier5, Rajendra Uprety2, Eyal Vardy1, Brian E Krumm1, Gye Won Han6, Ming-Yue Lee7, Els Pardon8, Jan Steyaert8, Xi-Ping Huang9, Ryan T Strachan1, Alexandra R Tribo1, Gavril W Pasternak2, F Ivy Carroll4, Raymond C Stevens10, Vadim Cherezov6, Vsevolod Katritch10, Daniel Wacker11, Bryan L Roth12.
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.Entities:
Keywords: GPCR; active state; addiction; crystallography; morphinan; nanobody; opioid receptor; structure-function
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Year: 2018 PMID： 29307491 PMCID： PMC5802374 DOI： 10.1016/j.cell.2017.12.011
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582