title: A rhodopsin-based model for melatonin recognition at its G protein-coupled receptor.
abstract: The recent elucidation of the primary structures of different melatonin receptors as well as the deduction of the secondary structure of rhodopsin has allowed us to construct a model for melatonin recognition at its G protein-coupled receptor. To achieve this, we have used the quantum 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 analysis (CoMFA) to generate a model for the structure-activity relationships of melatonin and 27 melatonin-like compounds. This model predicted 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 moieties with fully conserved amino acid residues present in transmembrane 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 structural features of melatonin and related active compounds.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kuopio, Finland. cecil.navajas@uku.fi
authors.forename: C
authors.initials: C
authors.lastname: Navajas
authors.forename: T
authors.initials: T
authors.lastname: Kokkola
authors.forename: A
authors.initials: A
authors.lastname: Poso
authors.forename: N
authors.initials: N
authors.lastname: Honka
authors.forename: J
authors.initials: J
authors.lastname: Gynther
authors.forename: J T
authors.initials: JT
authors.lastname: Laitinen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002645:Chickens; D019204:GTP-Binding Proteins / Q000378:metabolism*; D066298:In Vitro Techniques; D008550:Melatonin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism*; D044094:Receptors, Melatonin; D012243:Rhodopsin / Q000737:chemistry; D012756:Sheep; D013329:Structure-Activity Relationship
chemical_list: D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; D012243:Rhodopsin; D019204:GTP-Binding Proteins; D008550:Melatonin