20ZX

Cryo-EM structure of Gq-coupled LPAR5 in complex with LPA

Summary for 20ZX

• Entry DOI: 10.2210/pdb20zx/pdb
• EMDB information: 67439
• Descriptor: 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, Lysophosphatidic acid receptor 5, ... (6 entities in total)
• Functional Keywords: lpar5, lpa, membrane protein
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 5
• Total formula weight: 157775.71

Authors

Zhao, L.,Li, X. (deposition date: 2025-12-04, release date: 2026-06-17, Last modification date: 2026-07-01)

Primary citation

Li, X.,Wang, K.,Xing, Z.,Zhang, M.,Hu, W.,Yuan, Q.,Xu, H.E.,Zhao, L.H.
Structural basis for lysophosphatidic acid recognition and atypical G alpha q coupling by LPAR5.
Proc.Natl.Acad.Sci.USA, 123:-, 2026

PubMed Abstract: Lysophosphatidic acid receptor 5 (LPAR5) is a non-endothelial differentiation gene class A G protein-coupled receptor that regulates neuropathic pain, itch, and cancer progression through coupling to G proteins. Here, we report the cryo-EM structure of LPAR5 bound to 1-oleoyl-lysophosphatidic acid (LPA) in complex with G at 2.96 Å resolution, revealing a distinct mode of receptor activation and G protein coupling. The phosphate headgroup of LPA forms extensive polar interactions with residues from extracellular loop 2 and transmembrane helices TM5-TM7, while the lipid tail inserts into a deep hydrophobic cavity formed by TM3-TM5. Site-directed mutagenesis confirms the functional importance of these interactions. Remarkably, LPAR5 exhibits a noncanonical G protein coupling mode. Unlike previously reported GPCR-G protein structures in which the Gα C-terminal α5 helix ("wavy hook") primarily engages TM6, the wavy hook in LPAR5 is positioned toward the intracellular loop 1-helix 8 interface. This configuration is associated with limited TM6 outward displacement and modest rearrangement at the toggle-switch position (6.48). The resulting interface is stabilized by receptor-specific interactions and supported by functional data. Together, these findings reveal an alternative mode of GPCR-G protein coupling and highlight the structural plasticity underlying signaling specificity in LPA receptors.

PubMed: 42313925
DOI: 10.1073/pnas.2537482123

Experimental method

ELECTRON MICROSCOPY (2.96 Å)