Structure and function of the potent cyclic and linear melanocortin analogues |
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Authors: | Cho Min-Kyu Lee Chul-Jin Lee Chang-Hun Li Song-Zhe Lim Sung-Kil Baik Ja-Hyun Lee Weontae |
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Institution: | Department of Biochemistry, College of Science, Yonsei University, Seoul 120-749, Republic of Korea. |
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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. |
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Keywords: | Melanocortin Nuclear magnetic resonance Melanocortin receptor NDP-MSH |
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