Molecular basis for the interaction of [Nle4,D-Phe7]melanocyte stimulating hormone with the human melanocortin-1 receptor.

Yang Yk, Dickinson C, Haskell-Luevano C, Gantz I

The Journal of biological chemistry1 Sept 1997Cited by 36 (Europe PMC)

PMID9287296DOI10.1074/jbc.272.37.23000PepBankPUB-09287296

Publisher page PubMedAsk about this study

Summary

The melanocortin-1 receptor (MC1R) is a seven-transmembrane (TM) G-protein-coupled receptor whose natural ligands are the melanocortin peptides, adrenocorticotropic hormone, and alpha-, beta-, and gamma- melanocyte stimulating hormone (MSH). To test a previously constructed three-dimensional model of the molecular interaction between the long-acting, superpotent alpha-MSH analog [Nle4,D-Phe7]MSH (NDP-MSH) and the human MC1R we examined the effects of site-directed receptor mutagenesis on the binding affinity and potency of NDP-MSH. In addition, we also examined the effects of these same mutations on the binding affinity and potency of the structurally related agonists alpha-MSH, gamma-MSH, and Ac-Nle4-cyclic-[Asp5,His6,D-Phe7,Arg8,Trp9,Lys10]NH2 (MT-II). Mutagenesis of acidic receptor residues Glu94 in TM2 and Asp117 or Asp121 in TM3 significantly altered the binding affinity and potency of all four agonists suggesting that these receptor residues are important to the ligand-receptor interactions of all. A disproportionate change in agonist potency versus affinity observed with simultaneous mutation of these acidic residues (mutant constructs D117A/D121A or E94A/D117A/D121A) or introduction of a single positive charge (mutant construct D121K) also implicates these residues in receptor activation. In addition, results from the individual mutation of aromatic receptor residues Phe175, Phe196, and Phe257, and simultaneous mutation of multiple TM4, -5, and -6 tyrosine and phenylalanine residues suggests that aromatic-aromatic ligand-receptor interactions also participate in binding these melanocortins to the MC1R. These experiments appear to have identified some of the critical receptor residues involved in the ligand-receptor interactions between these melanocortins and the hMC1R.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study3

1 result from studies that gave the peptide. No result from this study comes from people.

01LabIn vitro (cells)Mechanism
Mutating the acidic receptor residues Glu94, Asp117 or Asp121 significantly altered the binding affinity and potency of MT-II and three other agonists at human MC1R.
In plain wordsIn cells, changing three amino acids in the MC1R receptor altered how well MT-II and other agonists bound and worked.
Peptide
Melanotan II
Outcome
Direction not reportedEffect of acidic MC1R residue mutations on MT-II binding and potency
Study
n: not reported in source
site-directed mutant human MC1R
Outcome group
Receptor activity and mechanism · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
Mutagenesis of acidic receptor residues Glu94 in TM2 and Asp117 or Asp121 in TM3 significantly altered the binding affinity and potency of all four agonists suggesting that these receptor residues are important to the ligand-receptor interactions of all.
2 context sentences(design, population, supporting numbers)
Summary · context
In addition, we also examined the effects of these same mutations on the binding affinity and potency of the structurally related agonists alpha-MSH, gamma-MSH, and Ac-Nle4-cyclic-[Asp5,His6,D-Phe7,Arg8,Trp9,Lys10]NH2 (MT-II).
Summary · context
To test a previously constructed three-dimensional model of the molecular interaction between the long-acting, superpotent alpha-MSH analog [Nle4,D-Phe7]MSH (NDP-MSH) and the human MC1R we examined the effects of site-directed receptor mutagenesis on the binding affinity and potency of NDP-MSH.
Show in the study text Report a problemFND-0928729601

Studies that did not test the peptide alone2

In this study, Melanotan II was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Melanotan II.

02LabNot a test of Melanotan II aloneIn vitro (cells)Mechanism
Simultaneous mutation of acidic residues, or a single positive charge at D121K, changed agonist potency out of proportion to affinity, implicating these residues in receptor activation.
In plain wordsIn cells, changes to key receptor amino acids affected how strongly agonists activated MC1R, beyond how well they bound.
Peptide
Melanotan II
Outcome
Not applicableAgonist potency versus affinity after acidic residue mutations
Study
n: not reported in source
site-directed mutant human MC1R
Outcome group
Receptor activity and mechanism · Pharmacology
Source sentences
Summary
A disproportionate change in agonist potency versus affinity observed with simultaneous mutation of these acidic residues (mutant constructs D117A/D121A or E94A/D117A/D121A) or introduction of a single positive charge (mutant construct D121K) also implicates these residues in receptor activation.
1 context sentence(design, population, supporting numbers)
Summary · context
To test a previously constructed three-dimensional model of the molecular interaction between the long-acting, superpotent alpha-MSH analog [Nle4,D-Phe7]MSH (NDP-MSH) and the human MC1R we examined the effects of site-directed receptor mutagenesis on the binding affinity and potency of NDP-MSH.
In this study, Melanotan II was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Melanotan II.
Show in the study text Report a problemFND-0928729602
03LabNot a test of Melanotan II aloneIn vitro (cells)Mechanism
Mutation of aromatic receptor residues suggests that aromatic-aromatic ligand-receptor interactions take part in binding melanocortins to MC1R.
In plain wordsIn cells, ring-shaped amino acids in the MC1R receptor appear to help melanocortins bind.
Peptide
Melanotan II
Outcome
Not applicableRole of aromatic MC1R residues in melanocortin binding
Study
n: not reported in source
site-directed mutant human MC1R
Outcome group
Receptor activity and mechanism · Pharmacology
Source sentences
Summary
In addition, results from the individual mutation of aromatic receptor residues Phe175, Phe196, and Phe257, and simultaneous mutation of multiple TM4, -5, and -6 tyrosine and phenylalanine residues suggests that aromatic-aromatic ligand-receptor interactions also participate in binding these melanocortins to the MC1R.
1 context sentence(design, population, supporting numbers)
Summary · context
To test a previously constructed three-dimensional model of the molecular interaction between the long-acting, superpotent alpha-MSH analog [Nle4,D-Phe7]MSH (NDP-MSH) and the human MC1R we examined the effects of site-directed receptor mutagenesis on the binding affinity and potency of NDP-MSH.
In this study, Melanotan II was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Melanotan II.
Show in the study text Report a problemFND-0928729603

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
10 Oct 2026, 09:43 UTC
Study results updated
Version 1
9 Oct 2026, 03:04 UTC
First added · source update from Europe PMC

Subjects

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