Structure and function of the potent cyclic and linear melanocortin analogues

Min Kyu Cho; Chul Jin Lee; Chang Hun Lee; Song Zhe Li; Sung Kil Lim; Ja Hyun Baik; Weontae Lee

doi:10.1016/j.jsb.2005.03.008

Structure and function of the potent cyclic and linear melanocortin analogues

Min Kyu Cho
, Chul Jin Lee
, Chang Hun Lee
, Song Zhe Li
, Sung Kil Lim
, Ja Hyun Baik
, Weontae Lee

Department of New Biology

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

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.

Original language	English
Pages (from-to)	300-308
Number of pages	9
Journal	Journal of Structural Biology
Volume	150
Issue number	3
DOIs	https://doi.org/10.1016/j.jsb.2005.03.008
State	Published - Jun 2005

Bibliographical note

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.).

Keywords

Melanocortin
Melanocortin receptor
NDP-MSH
Nuclear magnetic resonance

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jsb.2005.03.008

Cite this

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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.",

keywords = "Melanocortin, Melanocortin receptor, NDP-MSH, Nuclear magnetic resonance",

author = "Cho, \{Min Kyu\} and Lee, \{Chul Jin\} and Lee, \{Chang Hun\} and Li, \{Song Zhe\} and Lim, \{Sung Kil\} and Baik, \{Ja Hyun\} and Weontae Lee",

note = "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.).",

year = "2005",

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doi = "10.1016/j.jsb.2005.03.008",

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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.).

PY - 2005/6

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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

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IS - 3

ER -

Structure and function of the potent cyclic and linear melanocortin analogues

Abstract

Bibliographical note

Keywords

UN SDGs

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