A RHODOPSIN-BASED MODEL FOR MELATONIN RECOGNITION AT ITS G-PROTEIN-COUPLED RECEPTOR

The recent elucidation of the primary structures of different melatoni n receptors as well as the deduction of the secondary structure of rho dopsin has allowed us to construct a model for melatonin recognition a t its G protein-coupled receptor. To achieve this, we have used the qu antum mechanics method Austin model 1 to fully optimize the structures of melatonin and several analogs. We also synthesized three compounds and used the three-dimensional analysis comparative molecular field a nalysis (CoMFA) to generate a model for the structure-activity relatio nships of melatonin and 27 melatonin-like compounds. This model predic ted with good accuracy the affinities of the synthesized compounds for the melatonin receptor. We propose that recognition of the functional moieties of melatonin occurs through specific interaction of these mo ieties with fully conserved amino acid residues present in transmembra ne helices V, VI and VII of the melatonin receptor. These residues are not found in other members of the G protein-coupled receptor family. The rhodopsin-based model can explain the importance of some structura l features of melatonin and related active compounds.