title: Subtype selective binding properties of substituted linear melanocyte stimulating hormone analogues.
abstract: The melanocortin receptors are peptide binding G-protein coupled receptors that play a role in important physiological functions such as energy balance, inflammatory processes and several aspects of reproduction. In this study, we synthesised 11 new linear MSH analogues and tested their binding to the human MC receptors (MC1, MC3, MC4 and MC5) expressed in COS cells. Our results show that introduction of Asp in position 4 similarly affects the binding to the MC1, MC4 and MC5 receptors, but drastically lowers the binding to the MC3 receptor. Arg(5) substitution shows relatively high affinity for the MC4 receptor, while the results also give further support for specific importance of His(6) for the MC1 receptor. Introduction of Asp in position 10, mimicking gamma-MSH, decreased the affinity for the MC3 receptor in similar manner as for the MC4 receptor, suggesting that there are important differences in the binding conformation of gamma-MSH and NPD-MSH. Our results provide further information about the ligand binding requirements for each of the MC receptor subtypes, and highlights differential influence of the core residues in the MSH peptides. The data set also provides useful information for further calculations and modeling of MC receptor binders.
authors.affiliation: Department of Neuroscience, Biomedical Center, Uppsala University, Box 593, Uppsala 751 24, Sweden. helgis@bmc.uu.se
authors.forename: Helgi B
authors.initials: HB
authors.lastname: Schiöth
authors.forename: Aster
authors.initials: A
authors.lastname: Tesfaye
authors.forename: Felikss
authors.initials: F
authors.lastname: Mutulis
authors.forename: Richard
authors.initials: R
authors.lastname: Rudzish
authors.forename: Ilze
authors.initials: I
authors.lastname: Mutule
authors.forename: Ruta
authors.initials: R
authors.lastname: Muceniece
authors.forename: Hajime
authors.initials: H
authors.lastname: Watanobe
authors.forename: Jarl E S
authors.initials: JE
authors.lastname: Wikberg
mesh_terms: D019943:Amino Acid Substitution / Q000502:physiology; D001667:Binding, Competitive / Q000502:physiology; D002460:Cell Line; D006801:Humans; D009074:Melanocyte-Stimulating Hormones / Q000235:genetics / Q000378:metabolism*; D044102:Receptor, Melanocortin, Type 1 / Q000378:metabolism; D044104:Receptor, Melanocortin, Type 3 / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000378:metabolism; D018043:Receptors, Corticotropin / Q000378:metabolism; D044101:Receptors, Melanocortin / Q000378:metabolism*; D014162:Transfection
chemical_list: D044102:Receptor, Melanocortin, Type 1; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; C086971:melanocortin 5 receptor; D009074:Melanocyte-Stimulating Hormones