Description
Experimental Technique/Method:X-RAY DIFFRACTION
Resolution:3.1
Classification:MEMBRANE PROTEIN/AGONIST
Release Date:2018-01-17
Deposition Date:2017-10-03
Revision Date:2018-01-24
Molecular Weight:126051.35
Macromolecule Type:Protein
Residue Count:1104
Atom Site Count:6142
DOI:10.2210/pdb6b73/pdb
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.
Resolution:3.1
Classification:MEMBRANE PROTEIN/AGONIST
Release Date:2018-01-17
Deposition Date:2017-10-03
Revision Date:2018-01-24
Molecular Weight:126051.35
Macromolecule Type:Protein
Residue Count:1104
Atom Site Count:6142
DOI:10.2210/pdb6b73/pdb
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.
| Date made available | Jan 17 2018 |
|---|---|
| Publisher | RCSB-PDB |