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TitleStructural basis for the activation of proteinase-activated receptors PAR1 and PAR2.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 3931, Year 2025
Publish dateApr 26, 2025
AuthorsZongyang Lyu / Xiaoxuan Lyu / Andrey G Malyutin / Guliang Xia / Daniel Carney / Vinicius M Alves / Matthew Falk / Nidhi Arora / Hua Zou / Aaron P McGrath / Yanyong Kang /
PubMed AbstractMembers of the proteinase-activated receptor (PAR) subfamily of G protein-coupled receptors (GPCRs) play critical roles in processes like hemostasis, thrombosis, development, wound healing, ...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.
External linksNat Commun / PubMed:40287415 / PubMed Central
MethodsEM (single particle)
Resolution2.74 - 3.18 Å
Structure data

46448

9d0a

EMDB-46448, PDB-9d0a:
CryoEM structure of PAR2 with endogenous tethered ligand.
Method: EM (single particle) / Resolution: 3.1 Å

46571

9d4z

EMDB-46571, PDB-9d4z:
CryoEM structure of PAR1 with endogenous tethered ligand
Method: EM (single particle) / Resolution: 2.74 Å

47687

9e7r

EMDB-47687, PDB-9e7r:
CryoEM structure of PAR2 with GB88
Method: EM (single particle) / Resolution: 3.18 Å

Chemicals

PDB-1bf3:
P-HYDROXYBENZOATE HYDROXYLASE (PHBH) MUTANT WITH CYS 116 REPLACED BY SER (C116S) AND ARG 42 REPLACED BY LYS (R42K), IN COMPLEX WITH FAD AND 4-HYDROXYBENZOIC ACID

Source
  • homo sapiens (human)
  • unidentified (others)
  • mus musculus (house mouse)
KeywordsIMMUNE SYSTEM / PAR2 / endogenous ligand / endogenous ligand. / MEMBRANE PROTEIN/IMMUNE SYSTEM / GB88 / MEMBRANE PROTEIN-IMMUNE SYSTEM complex

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