Solution structures and molecular interactions of selective melanocortin receptor antagonists.
The solution structures and inter-molecular interaction of the cyclic melanocortin antagonists SHU9119, JKC363, HS014, and HS024 with receptor molecules have been determined by NMR spectroscopy and molecular modeling. While SHU9119 is known as a nonselective antagonist, JKC363, HS014, and HS024 are selective for the melanocortin subtype-4 receptor (MC4R) involved in modulation of food intake. Data from NMR and molecular dynamics suggest that the conformation of the Trp9 sidechain in the three MC4R-selective antagonists is quite different from that of SHU9119. This result strongly supports the concept that the spatial orientation of the hydrophobic aromatic residue is more important for determining selectivity than the presence of a basic, "arginine-like" moiety responsible for biological activity. We propose that the conformation of hydrophobic residues of MCR antagonists is critical for receptor-specific selectivity.
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Chul-Jin
CJ
Lee
Ji-Hye
JH
Yun
Sung-Kil
SK
Lim
Weontae
W
Lee
D000595:Amino Acid Sequence; D001665:Binding Sites; D004347:Drug Interactions; D057927:Hydrophobic and Hydrophilic Interactions; D009682:Magnetic Resonance Spectroscopy; D009074:Melanocyte-Stimulating Hormones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors* / Q000187:drug effects; D044101:Receptors, Melanocortin / Q000037:antagonists & inhibitors* / Q000187:drug effects; D012680:Sensitivity and Specificity; D012996:Solutions / Q000737:chemistry; D013329:Structure-Activity Relationship; D019824:beta-MSH / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
C471568:11-Mrp-14-Nal-18-Cys-22-Asp-beta-MSH(11-22)NH2; D010456:Peptides, Cyclic; D044105:Receptor, Melanocortin, Type 4; D044101:Receptors, Melanocortin; D012996:Solutions; D019824:beta-MSH; C103272:SHU 9119; D009074:Melanocyte-Stimulating Hormones