Volume 34, No 10, Oct 2024

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 34 Issue 10, October 2024: 725-734   |  Open Access

ORIGINAL ARTICLES

Structural basis of tethered agonism and G protein coupling of protease-activated receptors

Jia Guo^{1,2,3,4,5,†} , Yun-Li Zhou^1,† , Yixin Yang¹ , Shimeng Guo⁵ , Erli You⁵ , Xin Xie^5,6 , Yi Jiang⁷ , Chunyou Mao^3,4,8,* , H. Eric Xu^5,6 , Yan Zhang^1,2,3,4,9,*

¹Department of Pharmacology and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
²Liangzhu Laboratory, Zhejiang University, Hangzhou, Zhejiang, China
³Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
⁴Center for Structural Pharmacology and Therapeutics Development, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
⁵CAS Key Laboratory of Receptor Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
⁶University of Chinese Academy of Sciences, Beijing, China
⁷Lingang Laboratory, Shanghai, China
⁸Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Zhejiang University, Hangzhou, Zhejiang, China
⁹MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
^†These authors contributed equally: Jia Guo, Yun-Li Zhou
Correspondence: Chunyou Mao(eric.xu@simm.ac.cn)Yan Zhang(zhang_yan@zju.edu.cn)

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 Gq and Gi 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.

https://doi.org/10.1038/s41422-024-00997-2

FULL TEXT | PDF

Browse 398