Structure and function of the potent cyclic and linear melanocortin analogues

Min Kyu Cho, Chul Jin Lee, Chang Hun Lee, Song Zhe Li, Sungkil Lim, Ja Hyun Baik, Weon Tae Lee

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 languageEnglish
Pages (from-to)300-308
Number of pages9
JournalJournal of Structural Biology
Volume150
Issue number3
DOIs
Publication statusPublished - 2005 Jun 1

Fingerprint

Melanocortins
Melanocortin Receptors
Melanocyte-Stimulating Hormones
Ligands
Adenosine Monophosphate
Lysine
Proteins
Magnetic Resonance Spectroscopy
Obesity
Hormones
4-Nle-7-Phe-alpha-mSH
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Structural Biology

Cite this

Cho, Min Kyu ; Lee, Chul Jin ; Lee, Chang Hun ; Li, Song Zhe ; Lim, Sungkil ; Baik, Ja Hyun ; Lee, Weon Tae. / Structure and function of the potent cyclic and linear melanocortin analogues. In: Journal of Structural Biology. 2005 ; Vol. 150, No. 3. pp. 300-308.
@article{8b518431bd704da09c6bf79503c976a9,
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.",
author = "Cho, {Min Kyu} and Lee, {Chul Jin} and Lee, {Chang Hun} and Li, {Song Zhe} and Sungkil Lim and Baik, {Ja Hyun} and Lee, {Weon Tae}",
year = "2005",
month = "6",
day = "1",
doi = "10.1016/j.jsb.2005.03.008",
language = "English",
volume = "150",
pages = "300--308",
journal = "Journal of Structural Biology",
issn = "1047-8477",
publisher = "Academic Press Inc.",
number = "3",

}

Structure and function of the potent cyclic and linear melanocortin analogues. / Cho, Min Kyu; Lee, Chul Jin; Lee, Chang Hun; Li, Song Zhe; Lim, Sungkil; Baik, Ja Hyun; Lee, Weon Tae.

In: Journal of Structural Biology, Vol. 150, No. 3, 01.06.2005, p. 300-308.

Research output: Contribution to journalArticle

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, Sungkil

AU - Baik, Ja Hyun

AU - Lee, Weon Tae

PY - 2005/6/1

Y1 - 2005/6/1

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.

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

VL - 150

SP - 300

EP - 308

JO - Journal of Structural Biology

JF - Journal of Structural Biology

SN - 1047-8477

IS - 3

ER -