title: Structure and function of the potent cyclic and linear melanocortin analogues.
abstract: The MC3R and MC4R proteins comprise two melanocortin receptor subtypes that are involved in obesity, with each protein displaying a unique mechanism of action. To enable the design of a selective drug candidate, the solution structures of four peptidyl analogues of the melanocyte stimulating hormones, NDP-MSH, NDP-MSH(4-10) and two cyclic forms ([C5,C10]NDP-MSH(5-10), [C5,C10]NDP-MSH(5-11)), were characterized by two-dimensional nuclear magnetic resonance (NMR) spectroscopy and simulated annealing calculations. Using data from c-AMP assays in combination with structural analysis of melanocortin receptor/ligand models, we conclude that a lysine residue at the C-terminus of the His-Phe-Arg-Trp core sequence of melanocortin hormone is an important determinant for receptor selectivity in the both cyclic and linear MSH analogues. Our results suggest that side-chain orientation and charge-charge interactions with the ligand molecule play critical roles in receptor selectivity, whereas the overall backbone conformation or turn type contributes mainly to receptor binding.
authors.affiliation: Department of Biochemistry, College of Science, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Min-Kyu
authors.initials: MK
authors.lastname: Cho
authors.forename: Chul-Jin
authors.initials: CJ
authors.lastname: Lee
authors.forename: Chang-Hun
authors.initials: CH
authors.lastname: Lee
authors.forename: Song-Zhe
authors.initials: SZ
authors.lastname: Li
authors.forename: Sung-Kil
authors.initials: SK
authors.lastname: Lim
authors.forename: Ja-Hyun
authors.initials: JH
authors.lastname: Baik
authors.forename: Weontae
authors.initials: W
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009765:Obesity; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D051381:Rats; D044104:Receptor, Melanocortin, Type 3 / Q000737:chemistry; D044105:Receptor, Melanocortin, Type 4 / Q000737:chemistry; D044101:Receptors, Melanocortin / Q000737:chemistry / Q000378:metabolism; D055672:Static Electricity; D013329:Structure-Activity Relationship; D000521:alpha-MSH / Q000737:chemistry* / Q000502:physiology*
chemical_list: D008024:Ligands; D010455:Peptides; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D044101:Receptors, Melanocortin; D000521:alpha-MSH; D000242:Cyclic AMP