Structure and function of the potent cyclic and linear melanocortin analogues.
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.
Cho
Min-Kyu
MK
Department of Biochemistry, College of Science, Yonsei University, Seoul 120-749, Republic of Korea.
Lee
Chul-Jin
CJ
Lee
Chang-Hun
CH
Li
Song-Zhe
SZ
Lim
Sung-Kil
SK
Baik
Ja-Hyun
JH
Lee
Weontae
W
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*
D008024:Ligands; D010455:Peptides; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D044101:Receptors, Melanocortin; D000521:alpha-MSH; D000242:Cyclic AMP