Purinergic GPCR transmembrane residues involved in ligand recognition and dimerization

We compare the GPCR-ligand interactions and highlight important residues for recognition in purinergic receptors—from both X-ray crystallographic and cryo-EM structures. These include A1 and A2A adenosine receptors, and P2Y1 and P2Y12 receptors that respond to ADP and other nucleotides. These receptors are important drug discovery targets for immune, metabolic and nervous system disorders. In most cases, orthosteric ligands are represented, except for one allosteric P2Y1 antagonist. This review catalogs the residues and regions that engage in contacts with ligands or with other GPCR protomers in dimeric forms. Residues that are in proximity to bound ligands within purinergic GPCR families are correlated. There is extensive conservation of recognition motifs between adenosine receptors, but the P2Y1 and P2Y12 receptors are each structurally distinct in their ligand recognition. Identifying common interaction features for ligand recognition within a receptor class that has multiple structures available can aid in the drug discovery process.