Summary for 9E7R
| Entry DOI | 10.2210/pdb9e7r/pdb |
| Related | 9D0A 9D4Z |
| EMDB information | 47687 |
| Descriptor | Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, Proteinase-activated receptor 2, Guanine nucleotide-binding protein G(q) subunit alpha chimera, ... (6 entities in total) |
| Functional Keywords | par2, gb88, membrane protein-immune system complex, membrane protein/immune system |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 5 |
| Total formula weight | 151139.53 |
| Authors | Lyu, X.,Lyu, Z.,Malyutin, A.G.,McGrath, A.P.,Kang, Y. (deposition date: 2024-11-04, release date: 2025-05-07, Last modification date: 2025-05-21) |
| Primary citation | Lyu, 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: 40287415DOI: 10.1038/s41467-025-59138-x PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.18 Å) |
Structure validation
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