8XOS

Cryo-EM structure of the tethered agonist-bound human PAR1-Gi complex

Summary for 8XOS

• Entry DOI: 10.2210/pdb8xos/pdb
• EMDB information: 38539
• 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, membrane protein, protease-activated receptor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 189162.67

Authors

Guo, J.,Zhang, Y. (deposition date: 2024-01-02, release date: 2024-09-18, Last modification date: 2024-10-30)

Primary citation

Guo, J.,Zhou, Y.L.,Yang, Y.,Guo, S.,You, E.,Xie, X.,Jiang, Y.,Mao, C.,Xu, H.E.,Zhang, Y.
Structural basis of tethered agonism and G protein coupling of protease-activated receptors.
Cell Res., 34:725-734, 2024

PubMed Abstract: Protease-activated receptors (PARs) are a unique group within the G protein-coupled receptor superfamily, orchestrating cellular responses to extracellular proteases via enzymatic cleavage, which triggers intracellular signaling pathways. Protease-activated receptor 1 (PAR1) is a key member of this family and is recognized as a critical pharmacological target for managing thrombotic disorders. In this study, we present cryo-electron microscopy structures of PAR1 in its activated state, induced by its natural tethered agonist (TA), in complex with two distinct downstream proteins, the G and G heterotrimers, respectively. The TA peptide is positioned within a surface pocket, prompting PAR1 activation through notable conformational shifts. Contrary to the typical receptor activation that involves the outward movement of transmembrane helix 6 (TM6), PAR1 activation is characterized by the simultaneous downward shift of TM6 and TM7, coupled with the rotation of a group of aromatic residues. This results in the displacement of an intracellular anion, creating space for downstream G protein binding. Our findings delineate the TA recognition pattern and highlight a distinct role of the second extracellular loop in forming β-sheets with TA within the PAR family, a feature not observed in other TA-activated receptors. Moreover, the nuanced differences in the interactions between intracellular loops 2/3 and the Gα subunit of different G proteins are crucial for determining the specificity of G protein coupling. These insights contribute to our understanding of the ligand binding and activation mechanisms of PARs, illuminating the basis for PAR1's versatility in G protein coupling.

PubMed: 38997424
DOI: 10.1038/s41422-024-00997-2

Experimental method

ELECTRON MICROSCOPY (3.2 Å)