TY - JOUR
T1 - Structure and function of the potent cyclic and linear melanocortin analogues
AU - Cho, Min Kyu
AU - Lee, Chul Jin
AU - Lee, Chang Hun
AU - Li, Song Zhe
AU - Lim, Sung Kil
AU - Baik, Ja Hyun
AU - Lee, Weontae
N1 - Funding Information:
This work was supported by research grants from the Korean Ministry of Health and Welfare (01-PJ1-PG1-CH05-0005). This work was also supported by the NRL program of MOST NRDP (M1-0203-00-0020) and Korea Science and Engineering Foundation (KOSEF) through Protein Network Research Center at Yonsei University and in part by the Brain Korea 21 Project (W.L.).
Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2005/6
Y1 - 2005/6
N2 - 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.
AB - 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.
KW - Melanocortin
KW - Melanocortin receptor
KW - NDP-MSH
KW - Nuclear magnetic resonance
UR - http://www.scopus.com/inward/record.url?scp=18844446667&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=18844446667&partnerID=8YFLogxK
U2 - 10.1016/j.jsb.2005.03.008
DO - 10.1016/j.jsb.2005.03.008
M3 - Article
C2 - 15890278
AN - SCOPUS:18844446667
SN - 1047-8477
VL - 150
SP - 300
EP - 308
JO - Journal of Structural Biology
JF - Journal of Structural Biology
IS - 3
ER -
