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Structure paper

TitleMolecular mechanisms of inverse agonism via κ-opioid receptor-G protein complexes.
Journal, issue, pagesNat Chem Biol, Vol. 21, Issue 7, Page 1046-1057, Year 2025
Publish dateJan 7, 2025
AuthorsAaliyah S Tyson / Saif Khan / Zenia Motiwala / Gye Won Han / Zixin Zhang / Mohsen Ranjbar / Daniel Styrpejko / Nokomis Ramos-Gonzalez / Stone Woo / Kelly Villers / Delainey Landaker / Terry Kenakin / Ryan Shenvi / Susruta Majumdar / Cornelius Gati /
PubMed AbstractOpioid 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 ...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.
External linksNat Chem Biol / PubMed:39775170 / PubMed Central
MethodsEM (single particle)
Resolution3.0 - 3.58 Å
Structure data

43556

8vve

EMDB-43556, PDB-8vve:
Kappa opioid receptor:Galphai protein in complex with inverse agonist norBNI
Method: EM (single particle) / Resolution: 3.3 Å

43557

8vvf

EMDB-43557, PDB-8vvf:
Kappa opioid receptor:Galphai protein in complex with inverse agonist JDTic
Method: EM (single particle) / Resolution: 3.0 Å

43558

8vvg

EMDB-43558, PDB-8vvg:
Kappa opioid receptor in complex with heterotrimerig Gi protein, bound to inverse agonist GB18
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-43648: Kappa opioid receptor:Galphai protein in complex with inverse agonist JDTic, Original map receptor
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-43649: Kappa opioid receptor:Galphai protein in complex with inverse agonist JDTic, Original map G protein
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-43652: Kappa opioid receptor:Galphai protein in complex with inverse agonist norBNI, Original map G protein
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-43653: Kappa opioid receptor:Galphai protein in complex with inverse agonist GB18, Original map receptor
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-43654: Kappa opioid receptor:Galphai protein in complex with inverse agonist GB18, Original map G protein
Method: EM (single particle) / Resolution: 3.3 Å

46585

9d61

EMDB-46585, PDB-9d61:
Kappa opioid receptor:Galphai protein in complex with inverse agonist JDTic , no scFv16
Method: EM (single particle) / Resolution: 3.58 Å

Chemicals

PDB-1ad6:
DOMAIN A OF HUMAN RETINOBLASTOMA TUMOR SUPPRESSOR

ChemComp-JDC:
(3R)-7-hydroxy-N-{(2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]-3-methylbutan-2-yl}-1,2,3,4-tetrahydroisoquinoline-3-carboxamide / antagonist*YM

PDB-1ad5:
SRC FAMILY KINASE HCK-AMP-PNP COMPLEX

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / G protein coupled receptor / Opioid receptor

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