Yun-Li Zhou’s research while affiliated with Zhejiang Medical University and other places

What is this page?


This page lists works of an author who doesn't have a ResearchGate profile or hasn't added the works to their profile yet. It is automatically generated from public (personal) data to further our legitimate goal of comprehensive and accurate scientific recordkeeping. If you are this author and want this page removed, please let us know.

Publications (1)


Fig. 2 Intramolecular interactions of the TA. a The TA-binding pocket in PAR1. b-f Detailed interactions between the TA and the transmembrane core of PAR1. Side chains of residues are displayed in sticks. Hydrogen bonds are depicted as red dashed lines, the salt bridge is depicted as a orange dashed line. g Effects of mutations of residues in the binding pocket on Gα q -Gγ dissociation induced by the synthesized TA peptide. ΔpEC 50 represents the difference between pEC 50 values of the mutant PAR1 receptor and the wild-type (WT) receptor. Data are presented as means ± SEM of more than three independent experiments performed in technical triplicate. NS, P ≥ 0.05, *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001 by one-way ANOVA followed by Fisher's LSD multiple comparisons test compared with WT PAR1. h Comparison between the efficacy of PAR1 signaling activated by thrombin and the synthesized TA peptide. The efficacy is defined as the range between the maximal response (E max ) and the vehicle baseline (no agonist). Data are presented as means ± SEM of more than three independent experiments performed in technical triplicate. NS, P ≥ 0.05, *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001 by two-way ANOVA. A detailed statistical evaluation is provided in Supplementary information, Fig. S4 and Tables S3, S4.
Fig. 3 Activation mechanism of PAR1. a Superposition of the TA-bound PAR1 structure (teal) with the inactive PAR1 structure (gray) (PDB: 3VW7 10 ). b Comparison of the binding pocket of the TA and the antagonist vorapaxar in PAR1. c Conformational changes of Y95N N-term and Y350 7.32 induced by F43 TA-02 upon TA binding. d The rearrangement of local residues in the backbone of TMD in TA-bound PAR1 compared to the inactive structure shows the cascade changes of residues H336 6.58 , Y337 6.59 , Y353 7.35 , F271 5.39 , Y183 3.33 , F182 3.32 , M186 3.36 , and I190 3.40 . e The "K-R-K" motif involved in activation signal transmission of PAR1. The "K-R-K" motif consists of K135 2.37 , R200 3.50 , and K307 6.29 of PAR1. f Sequence alignment of residues involved in the activation of PAR family receptors. g Mutations of F182 3.32 , Y183 3.33 , M186 3.36 , F271 5.39 , H336 6.58 , Y337 6.59 , and Y353 7.35 in PAR1 decreased the activation potency induced by the TA peptide. Data represent the means ± SEM from three biologically independent experiments performed in triplicate. A detailed statistical evaluation is provided in Supplementary information, Table S5.
Fig. 4 G protein selectivity mediated by ICLs of PAR1. a Structural superposition of the TA-PAR1-G q and TA-PAR1-G i complexes. b Differences in the interactions between ICL3 with Gα q and Gα i . c Effects of mutations in ICL3 on Gα q -Gγ and Gα i -Gγ dissociation induced by the synthesized TA peptide. d, e The positioning of PAR1 ICL2 within the hydrophobic cavities of Gα q (d) and Gα i (e), respectively. The light yellow color indicates hydrophobicity. f Effects of mutations in ICL2 on Gα q -Gγ and Gα i -Gγ dissociation induced by the synthesized TA peptide. A detailed statistical evaluation is provided in Supplementary information, Tables S6 and S7.
Structural basis of tethered agonism and G protein coupling of protease-activated receptors
  • Article
  • Full-text available

July 2024

·

86 Reads

·

2 Citations

Cell Research

Jia Guo

·

Yun-Li Zhou

·

Yixin Yang

·

[...]

·

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 q and G i 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.

Download

Citations (1)


... Structural biology approaches like crystallography and cryo-electron microscopy (cryo-EM) have uncovered the functions of platelet membrane proteins by obtaining high-resolution structures of Gprotein coupled receptors, adhesion molecules, and other surface receptors. [8][9][10] They have also uncovered the binding sites and mechanisms of anti-platelet therapies. 11,12 However, to understand the impact of native environment, we need approaches beyond traditional structural biology. ...

Reference:

Elucidating the dynamics of Integrin αIIb[beta]3 from native platelet membranes by cryo-EM with build and retrieve method
Structural basis of tethered agonism and G protein coupling of protease-activated receptors

Cell Research