7PP1

Crystal structure of the P2Y12 receptor in complex with the inverse agonist selatogrel.

This is a non-PDB format compatible entry.

Summary for 7PP1

• Entry DOI: 10.2210/pdb7pp1/pdb
• Descriptor: P2Y purinoceptor 12,Soluble cytochrome b562,P2Y purinoceptor 12, Selatogrel, CHOLESTEROL, ... (4 entities in total)
• Functional Keywords: inverse agonist, complex, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 54254.15

Authors

Mac Sweeney, A.,Tidten-Luksch, N. (deposition date: 2021-09-13, release date: 2022-11-02, Last modification date: 2024-10-23)

Primary citation

Pons, V.,Garcia, C.,Tidten-Luksch, N.,Mac Sweeney, A.,Caroff, E.,Gales, C.,Riederer, M.A.
Inverse agonist efficacy of selatogrel blunts constitutive P2Y12 receptor signaling by inducing the inactive receptor conformation.
Biochem Pharmacol, 206:115291-115291, 2022

PubMed Abstract: Selatogrel is a potent inhibitor of adenosine diphosphate (ADP) binding to the P2Y12 receptor, preventing platelet activation. We have previously shown that the P2Y12 receptor constitutively activates Gi- and Go-protein-mediated signaling in human platelets. Here, we report that selatogrel acts as an inverse agonist of the P2Y12 receptor. Specifically, using bioluminescence resonance energy transfer2 (BRET2) probes, selatogrel, ticagrelor, and elinogrel were shown to stabilize the inactive form of the Gi/o-G complex in cells with recombinant expression of the P2Y12 receptor. In dose-response experiments, while selatogrel exhibited a maximal efficacy similar to ticagrelor, selatogrel was approximately 100-fold more potent than ticagrelor. Quantification of relative cyclic adenosine monophosphate (cAMP) levels in cells expressing the cAMP BRET1 sensor (CAMYEL probe) confirmed that selatogrel completely abolished the constitutive activity of the P2Y12 receptor. In agreement, selatogrel increased basal cAMP levels in human platelets, confirming inverse agonism on the endogenous human platelet P2Y12 receptor. In agreement with the biochemical phenotype of inverse agonism efficacy of selatogrel, the 2.8 Angstrom resolution cocrystal structure of selatogrel bound to the P2Y12 receptor confirmed that selatogrel stabilizes the inactive, basal state of the receptor. Selatogrel bound to pocket 1, spanning helix III to VII. Furthermore, the binding mode of selatogrel, suggesting steric overlap with the proposed binding site of ADP and the ADP analog 2-methylthioadenosine diphosphate (2MeSADP), agrees with the functional characterization of selatogrel preventing platelet activation by blocking ADP binding to the P2Y12 receptor.

PubMed: 36306820
DOI: 10.1016/j.bcp.2022.115291

Experimental method

X-RAY DIFFRACTION (2.78 Å)