Solution Structures of Cyclic Melanocortin Agonists and Antagonists by NMR

Jinfa Ying, Katalin E. Kövér, Xuyuan Gu, Guoxia Han, Dev B. Trivedi, Malcolm J. Kavarana, Victor J Hruby

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

The melanocortin receptors are involved in many physiological functions, including pigmentation, sexual function, feeding behavior, and energy homeostasis, making them potential targets for drugs to treat obesity, sexual dysfunction, etc. Understanding the conformational basis of the receptor-ligand interactions is crucial to the design of potent and selective ligands for these receptors. The solution structures of the cyclic melanocortin agonists, partial agonist, and antagonists MTII, VJH085, SHU9II9, MK5, and MK9 were determined by two-dimensional nuclear magnetic resonance (2D NMR) spectroscopy at pH 4.5 and 25 °C in water (90% H2O/10% D2O). The overall backbone structures of these cyclic α-melanocyte-stimulating hormone (α-MSH) analogues around the message sequence (His6-D-Phe 7/D-Nal(2′)7-Arg8-Trp9) were similar and reasonably well defined. β-Turns spanning His6 and D-Phe7/D-Nal(2′)7 were identified in all analogues, and an amphiphilic molecular surface was obtained for the message sequence residues in most structures within the NMR ensembles. The β-turn, which most closely resembles a type II β-turn, leads to stacking between the aromatic rings of His6 and D-Phe7 in MTII and VJH085. However, no aromatic stacking between His6 and D-Nal(2′) 7 was found in structures of the D-Nal(2′) 7-containing analogues. The difference in the side-chain dispositions of His6 and D-Nal(2′)7 may be responsible for the reduced potency or antagonist activity of the D-Nal(2′)7-containing analogues. In addition, our results suggest that the side-chain orientations may also modulate the receptor selectivity. The information found in this study will be useful for the further design of ligands for melanocortin receptors.

Original languageEnglish (US)
Pages (from-to)696-716
Number of pages21
JournalBiopolymers - Peptide Science Section
Volume71
Issue number6
DOIs
StatePublished - 2003

Fingerprint

Melanocortins
Melanocortin Receptors
Ligands
Nuclear magnetic resonance
Magnetic Resonance Spectroscopy
Magnetic resonance spectroscopy
Melanocyte-Stimulating Hormones
Hormones
Pigmentation
Feeding Behavior
Nuclear magnetic resonance spectroscopy
Homeostasis
Obesity
Water
Pharmaceutical Preparations

Keywords

  • α-MSH
  • β-turns
  • Conformation/bioactivity relationships
  • Melanocortin receptors
  • NMR
  • Torsion-angle dynamics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Biophysics

Cite this

Solution Structures of Cyclic Melanocortin Agonists and Antagonists by NMR. / Ying, Jinfa; Kövér, Katalin E.; Gu, Xuyuan; Han, Guoxia; Trivedi, Dev B.; Kavarana, Malcolm J.; Hruby, Victor J.

In: Biopolymers - Peptide Science Section, Vol. 71, No. 6, 2003, p. 696-716.

Research output: Contribution to journalArticle

Ying, J, Kövér, KE, Gu, X, Han, G, Trivedi, DB, Kavarana, MJ & Hruby, VJ 2003, 'Solution Structures of Cyclic Melanocortin Agonists and Antagonists by NMR', Biopolymers - Peptide Science Section, vol. 71, no. 6, pp. 696-716. https://doi.org/10.1002/bip.10596
Ying, Jinfa ; Kövér, Katalin E. ; Gu, Xuyuan ; Han, Guoxia ; Trivedi, Dev B. ; Kavarana, Malcolm J. ; Hruby, Victor J. / Solution Structures of Cyclic Melanocortin Agonists and Antagonists by NMR. In: Biopolymers - Peptide Science Section. 2003 ; Vol. 71, No. 6. pp. 696-716.
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