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Structural basis for the activation of proteinase-activated receptors PAR1 and PAR2

Author

Listed:
  • Zongyang Lyu

    (9625 Towne Centre Drive)

  • Xiaoxuan Lyu

    (9625 Towne Centre Drive)

  • Andrey G. Malyutin

    (9625 Towne Centre Drive)

  • Guliang Xia

    (9625 Towne Centre Drive)

  • Daniel Carney

    (9625 Towne Centre Drive)

  • Vinicius M. Alves

    (9625 Towne Centre Drive)

  • Matthew Falk

    (9625 Towne Centre Drive)

  • Nidhi Arora

    (9625 Towne Centre Drive)

  • Hua Zou

    (9625 Towne Centre Drive)

  • Aaron P. McGrath

    (9625 Towne Centre Drive)

  • Yanyong Kang

    (9625 Towne Centre Drive)

Abstract

Members of the proteinase-activated receptor (PAR) subfamily of G protein-coupled receptors (GPCRs) play critical roles in processes like hemostasis, thrombosis, development, wound healing, inflammation, and cancer progression. Comprising PAR1-PAR4, these receptors are specifically activated by protease cleavage at their extracellular amino terminus, revealing a ‘tethered ligand’ that self-activates the receptor. This triggers complex intracellular signaling via G proteins and beta-arrestins, linking external protease signals to cellular functions. To date, direct structural visualization of these ligand-receptor complexes has been limited. Here, we present structural snapshots of activated PAR1 and PAR2 bound to their endogenous tethered ligands, revealing a shallow and constricted orthosteric binding pocket. Comparisons with antagonist-bound structures show minimal conformational changes in the TM6 helix and larger movements of TM7 upon activation. These findings reveal a common activation mechanism for PAR1 and PAR2, highlighting critical residues involved in ligand recognition. Additionally, the structure of PAR2 bound to a pathway selective antagonist, GB88, demonstrates how potent orthosteric engagement can be achieved by a small molecule mimicking the endogenous tethered ligand’s interactions.

Suggested Citation

  • Zongyang Lyu & Xiaoxuan Lyu & Andrey G. Malyutin & Guliang Xia & Daniel Carney & Vinicius M. Alves & Matthew Falk & Nidhi Arora & Hua Zou & Aaron P. McGrath & Yanyong Kang, 2025. "Structural basis for the activation of proteinase-activated receptors PAR1 and PAR2," Nature Communications, Nature, vol. 16(1), pages 1-10, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59138-x
    DOI: 10.1038/s41467-025-59138-x
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