8X3L

Cryo-EM structure of CB2-G protein complex

Summary for 8X3L

• Entry DOI: 10.2210/pdb8x3l/pdb
• EMDB information: 38039
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-1, 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: gpcr, cb2, gi1, membrane protein, membrane protein-immune system complex, membrane protein/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 151778.11

Authors

Shen, S.Y.,Yang, Z.Q.,Shao, Z.H. (deposition date: 2023-11-14, release date: 2024-11-20, Last modification date: 2025-12-24)

Primary citation

Yang, X.,Zhou, P.,Shen, S.,Hu, Q.,Tian, C.,Xia, A.,Wang, Y.,Yang, Z.,Nan, J.,Zhou, Y.,Chen, S.,Tian, X.,Wu, C.,Lin, G.,Zhang, L.,Wang, K.,Zheng, T.,Zou, J.,Yan, W.,Shao, Z.,Yang, S.
Entropy drives the ligand recognition in G-protein-coupled receptor subtypes.
Proc.Natl.Acad.Sci.USA, 121:e2401091121-e2401091121, 2024

PubMed Abstract: Achieving ligand subtype selectivity within highly homologous subtypes of G-protein-coupled receptor (GPCR) is critical yet challenging for GPCR drug discovery, primarily due to the unclear mechanism underlying ligand subtype selectivity, which hampers the rational design of subtype-selective ligands. Herein, we disclose an unusual molecular mechanism of entropy-driven ligand recognition in cannabinoid (CB) receptor subtypes, revealed through atomic-level molecular dynamics simulations, cryoelectron microscopy structure, and mutagenesis experiments. This mechanism is attributed to the distinct conformational dynamics of the receptor's orthosteric pocket, leading to variations in ligand binding entropy and consequently, differential binding affinities, which culminate in specific ligand recognition. We experimentally validated this mechanism and leveraged it to design ligands with enhanced or ablated subtype selectivity. One such ligand demonstrated favorable pharmacokinetic properties and significant efficacy in rodent inflammatory analgesic models. More importantly, it is precisely due to the high subtype selectivity obtained based on this mechanism that this ligand does not show addictive properties in animal models. Our findings elucidate the unconventional role of entropy in CB receptor subtype selectivity and suggest a strategy for rational design of ligands to achieve entropy-driven subtype selectivity for many pharmaceutically important GPCRs.

PubMed: 39024109
DOI: 10.1073/pnas.2401091121

Experimental method

ELECTRON MICROSCOPY (3.13 Å)