Cannabinoid Receptor: Evidence for a Serine-Induced Bend in CB1 Transmembrane Helix 7

Ligands of structurally diverse natures are able to bind at the CB1 cannabinoid receptor, suggesting the existence of multiple binding sites on the receptor. Modeling studies have implicated Ser2.60(173) and Ser7.39(383) as possible interaction site(s) for CB1 agonists. To test the importance of these residues for receptor recognition, recombinant human CB1 receptors, sta-bly expressed in human embryonic kidney 293 cells, were used to investigate the consequences of mutating Ser2.60 (to S2.60A) or Ser7.39 (to S7.39A) in radioligand binding and guanosine 5-3-O-(thio)triphosphate functional assays. The S7.39A mutant resulted in a total ablation of [3H]()-3-[2-hy-droxyl-4-(1,1-dimethylheptyl)phenyl]-4-[3-hydroxylpropyl] cy-clohexan-1-ol (CP55,940) high-affinity binding. However, [3H](R)-()-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]