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9D0A

CryoEM structure of PAR2 with endogenous tethered ligand.

Summary for 9D0A
Entry DOI10.2210/pdb9d0a/pdb
EMDB information46448
DescriptorGuanine 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, scFv16, ... (5 entities in total)
Functional Keywordspar2, endogenous ligand, immune system
Biological sourceHomo sapiens (human)
More
Total number of polymer chains5
Total formula weight156615.68
Authors
Lyu, Z.,Lyu, X.,McGrath, A.P.,Kang, Y. (deposition date: 2024-08-06, release date: 2025-05-07, Last modification date: 2025-05-28)
Primary citationLyu, Z.,Lyu, X.,Malyutin, A.G.,Xia, G.,Carney, D.,Alves, V.M.,Falk, M.,Arora, N.,Zou, H.,McGrath, A.P.,Kang, Y.
Structural basis for the activation of proteinase-activated receptors PAR1 and PAR2.
Nat Commun, 16:3931-3931, 2025
Cited by
PubMed 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.
PubMed: 40287415
DOI: 10.1038/s41467-025-59138-x
PDB entries with the same primary citation
Experimental method
ELECTRON MICROSCOPY (3.1 Å)
Structure validation

238895

数据于2025-07-16公开中

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