9PY2

Engaged-state loperamide-mu opioid receptor-Gi GDPbS complex (rebound)

This is a non-PDB format compatible entry.

Summary for 9PY2

• Entry DOI: 10.2210/pdb9py2/pdb
• EMDB information: 72006
• Descriptor: Soluble cytochrome b562,Mu-type opioid receptor, Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (7 entities in total)
• Functional Keywords: g protein coupled receptor, mu opioid receptor, loperamide, membrane protein, gdp
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 159365.62

Authors

Gati, C.,Han, G.W.,Khan, S. (deposition date: 2025-08-06, release date: 2025-11-12, Last modification date: 2025-11-19)

Primary citation

Khan, S.,Tyson, A.S.,Ranjbar, M.,Zhang, Z.,Singh, J.,Han, G.W.,Gati, C.
Structural snapshots capture nucleotide release at the mu-opioid receptor.
Nature, 2025

PubMed Abstract: As a member of the G protein-coupled receptor superfamily, the μ-opioid receptor (MOR) activates heterotrimeric G proteins by opening the Gα α-helical domain (AHD) to enable GDP-GTP exchange, with GDP release representing the rate-limiting step. Here, using pharmacological assays, we show that agonist efficacy correlates with decreased GDP affinity, promoting GTP exchange, whereas antagonists increase GDP affinity, dampening activation. Further investigating this phenomenon, we provide 8 unique structural models and 16 cryogenic electron microscopy maps of MOR with naloxone or loperamide, capturing several intermediate conformations along the activation pathway. These include four GDP-bound states with previously undescribed receptor-G protein interfaces, AHD arrangements and transitions in the nucleotide-binding pocket required for GDP release. Naloxone stalls MOR in a 'latent' state, whereas loperamide promotes an 'engaged' state, which is structurally poised for opening of the AHD domain and subsequent GDP release. These findings, supported by molecular dynamics simulations, identify GDP-bound intermediates and AHD conformations as key determinants of nucleotide exchange rates, providing structural and mechanistic insights into G protein activation and ligand efficacy with broad implications for G protein-coupled receptor pharmacology.

PubMed: 41193810
DOI: 10.1038/s41586-025-09677-6

Experimental method

ELECTRON MICROSCOPY (3.16 Å)