8VVE

Kappa opioid receptor:Galphai protein in complex with inverse agonist norBNI

This is a non-PDB format compatible entry.

Summary for 8VVE

• Entry DOI: 10.2210/pdb8vve/pdb
• EMDB information: 43556
• Descriptor: Kappa-type opioid receptor, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: g protein coupled receptor, opioid receptor, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 155715.63

Authors

Gati, C.,Motiwala, Z.,Tyson, A.S.,Styrpejko, D.,Han, G.W.,Khan, S.,Ramos-Gonzalez, N.,Shenvi, R.,Majumdar, S. (deposition date: 2024-01-31, release date: 2025-01-15, Last modification date: 2025-05-28)

Primary citation

Tyson, A.S.,Khan, S.,Motiwala, Z.,Han, G.W.,Zhang, Z.,Ranjbar, M.,Styrpejko, D.,Ramos-Gonzalez, N.,Woo, S.,Villers, K.,Landaker, D.,Kenakin, T.,Shenvi, R.,Majumdar, S.,Gati, C.
Molecular mechanisms of inverse agonism via kappa-opioid receptor-G protein complexes.
Nat.Chem.Biol., 2025

PubMed Abstract: Opioid receptors, a subfamily of G protein-coupled receptors (GPCRs), are key therapeutic targets. In the canonical GPCR activation model, agonist binding is required for receptor-G protein complex formation, while antagonists prevent G protein coupling. However, many GPCRs exhibit basal activity, allowing G protein association without an agonist. The pharmacological impact of agonist-free receptor-G protein complexes is poorly understood. Here we present biochemical evidence that certain κ-opioid receptor (KOR) inverse agonists can act via KOR-G protein complexes. To investigate this phenomenon, we determined cryo-EM structures of KOR-G protein complexes with three inverse agonists: JDTic, norBNI and GB18, corresponding to structures of inverse agonist-bound GPCR-G protein complexes. Remarkably, the orthosteric binding pocket resembles the G protein-free 'inactive' receptor conformation, while the receptor remains coupled to the G protein. In summary, our work challenges the canonical model of receptor antagonism and offers crucial insights into GPCR pharmacology.

PubMed: 39775170
DOI: 10.1038/s41589-024-01812-0

Experimental method

ELECTRON MICROSCOPY (3.3 Å)