6B73

Crystal Structure of a nanobody-stabilized active state of the kappa-opioid receptor

Summary for 6B73

• Entry DOI: 10.2210/pdb6b73/pdb
• Descriptor: Soluble cytochrome b562, kappa-type opioid receptor, Nanobody, N-[(5alpha,6beta)-17-(cyclopropylmethyl)-3-hydroxy-7,8-didehydro-4,5-epoxymorphinan-6-yl]-3-iodobenzamide, ... (5 entities in total)
• Functional Keywords: gpcr, opioid receptor, addiction, active state, nanobody, structure-function, morphinan, lcp, membrane protein, membrane protein-agonist complex, membrane protein/agonist
• Biological source: Escherichia coli; More
• Total number of polymer chains: 4
• Total formula weight: 126051.35

Authors

Che, T.,Majumdar, S.,Zaidi, S.A.,Kormos, C.,McCorvy, J.D.,Wang, S.,Mosier, P.D.,Uprety, R.,Vardy, E.,Krumm, B.E.,Han, G.W.,Lee, M.Y.,Pardon, E.,Steyaert, J.,Huang, X.P.,Strachan, R.T.,Tribo, A.R.,Pasternak, G.W.,Carroll, I.F.,Stevens, R.C.,Cherezov, V.,Katritch, V.,Wacker, D.,Roth, B.L. (deposition date: 2017-10-03, release date: 2018-01-17, Last modification date: 2024-10-30)

Primary citation

Che, T.,Majumdar, S.,Zaidi, S.A.,Ondachi, P.,McCorvy, J.D.,Wang, S.,Mosier, P.D.,Uprety, R.,Vardy, E.,Krumm, B.E.,Han, G.W.,Lee, M.Y.,Pardon, E.,Steyaert, J.,Huang, X.P.,Strachan, R.T.,Tribo, A.R.,Pasternak, G.W.,Carroll, F.I.,Stevens, R.C.,Cherezov, V.,Katritch, V.,Wacker, D.,Roth, B.L.
Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor.
Cell, 172:55-67.e15, 2018

PubMed 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.

PubMed: 29307491
DOI: 10.1016/j.cell.2017.12.011

Experimental method

X-RAY DIFFRACTION (3.1 Å)