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Study · Not a test of the peptide alone · 2010

4 results

Interactions of the melanocortin-4 receptor with the peptide agonist NDP-MSH.

Chapman KL, Kinsella GK, Cox A, Donnelly D, Findlay JB

Journal of molecular biology19 Jun 2010Cited by 19 (Europe PMC)

PMID20600126 (opens in a new tab)PMCIDPMC3101337 (opens in a new tab)DOI10.1016/j.jmb.2010.06.028 (opens in a new tab)PepBankPUB-20600126
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Summary

Melanocortin-4 receptor (MC4R) has an important regulatory role in energy homeostasis and food intake. Peptide agonists of the MC4R are characterized by the conserved sequence His(6)-Phe(7)-Arg(8)-Trp(9), which is crucial for their interaction with the receptor. This investigation utilized the covalent attachment approach to identify receptor residues in close proximity to the bound ligand [Nle(4),D-Phe(7)]melanocyte-stimulating hormone (NDP-MSH), thereby differentiating between residues directly involved in ligand binding and those mutations that compromise ligand binding by inducing conformational changes in the receptor. Also, recent X-ray structures of G-protein-coupled receptors were utilized to refine a model of human MC4R in the active state (R(*)), which was used to generate a better understanding of the binding mode of the ligand NDP-MSH at the atomic level. The mutation of residues in the human MC4R--such as Leu106 of extracellular loop 1, and Asp122, Ile125, and Asp126 of transmembrane (TM) helix 3, His264 (TM6), and Met292 (TM7)--to Cys residues produced definitive indications of proximity to the side chains of residues in the core region of the peptide ligand. Of particular interest was the contact between D-Phe(7) on the ligand and Ile125 of TM3 on the MC4R. Additionally, Met292 (TM7) equivalent to Lys(7.45) (Ballesteros numbering scheme) involved in covalently attaching retinal in rhodopsin is shown to be in close proximity to Trp(9). For the first time, the interactions between the terminal regions of NDP-MSH and the receptor are described. The amino-terminus appears to be adjacent to a series of hydrophilic residues with novel interactions at Cys196 (TM5) and Asp189 (extracellular loop 2). These interactions are reminiscent of sequential ligand binding exhibited by the beta(2)-adrenergic receptor, with the former interaction being equivalent to the known interaction involving Ser204 of the beta(2)-adrenergic receptor.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study4

No result from this study comes from a test of the peptide.

Studies that did not test the peptide alone4

In this study, Melanotan I (afamelanotide) 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 I (afamelanotide).

  1. 01LabNot a test of Melanotan I (afamelanotide) aloneOther designMechanism

    Cysteine substitutions at six residues of human MC4R (Leu106, Asp122, Ile125, Asp126, His264, Met292) gave definitive indications of proximity to side chains in the core region of NDP-MSH.

    In plain wordsIn lab tests, six spots on the MC4R receptor were shown to sit close to the core of the bound NDP-MSH peptide.

    Peptide
    Melanotan I (afamelanotide)
    Outcome
    Not applicableReceptor residues in proximity to bound NDP-MSH
    Study

    humann: not reported in source

    Mutant human MC4R with cysteine substitutions (covalent attachment approach)
    Outcome group
    Receptor activity and mechanism · Pharmacology

    Source sentences

    Summary
    The mutation of residues in the human MC4R--such as Leu106 of extracellular loop 1, and Asp122, Ile125, and Asp126 of transmembrane (TM) helix 3, His264 (TM6), and Met292 (TM7)--to Cys residues produced definitive indications of proximity to the side chains of residues in the core region of the peptide ligand.
    1 context sentence
    Summary · context
    This investigation utilized the covalent attachment approach to identify receptor residues in close proximity to the bound ligand [Nle(4),D-Phe(7)]melanocyte-stimulating hormone (NDP-MSH), thereby differentiating between residues directly involved in ligand binding and those mutations that compromise ligand binding by inducing conformational changes in the receptor.

    In this study, Melanotan I (afamelanotide) 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 I (afamelanotide).

  2. 02LabNot a test of Melanotan I (afamelanotide) aloneOther designMechanism

    The D-Phe(7) of NDP-MSH was in contact with Ile125 in transmembrane helix 3 of MC4R.

    In plain wordsIn lab tests, one part of the NDP-MSH peptide touched a specific spot on the MC4R receptor.

    Peptide
    Melanotan I (afamelanotide)
    Outcome
    Not applicableContact between D-Phe(7) of NDP-MSH and Ile125 of MC4R
    Study

    humann: not reported in source

    Mutant human MC4R with cysteine substitutions (covalent attachment approach)
    Outcome group
    Receptor activity and mechanism · Pharmacology

    Source sentences

    Summary
    Of particular interest was the contact between D-Phe(7) on the ligand and Ile125 of TM3 on the MC4R.
    1 context sentence
    Summary · context
    This investigation utilized the covalent attachment approach to identify receptor residues in close proximity to the bound ligand [Nle(4),D-Phe(7)]melanocyte-stimulating hormone (NDP-MSH), thereby differentiating between residues directly involved in ligand binding and those mutations that compromise ligand binding by inducing conformational changes in the receptor.

    In this study, Melanotan I (afamelanotide) 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 I (afamelanotide).

  3. 03LabNot a test of Melanotan I (afamelanotide) aloneOther designMechanism

    Met292 in transmembrane helix 7 of MC4R was in close proximity to Trp(9) of NDP-MSH.

    In plain wordsIn lab tests, a spot in the MC4R receptor sat close to the Trp(9) part of the NDP-MSH peptide.

    Peptide
    Melanotan I (afamelanotide)
    Outcome
    Not applicableProximity of MC4R Met292 (TM7) to Trp(9) of NDP-MSH
    Study

    humann: not reported in source

    Mutant human MC4R with cysteine substitutions (covalent attachment approach)
    Outcome group
    Receptor activity and mechanism · Pharmacology

    Source sentences

    Summary
    Additionally, Met292 (TM7) equivalent to Lys(7.45) (Ballesteros numbering scheme) involved in covalently attaching retinal in rhodopsin is shown to be in close proximity to Trp(9).
    1 context sentence
    Summary · context
    This investigation utilized the covalent attachment approach to identify receptor residues in close proximity to the bound ligand [Nle(4),D-Phe(7)]melanocyte-stimulating hormone (NDP-MSH), thereby differentiating between residues directly involved in ligand binding and those mutations that compromise ligand binding by inducing conformational changes in the receptor.

    In this study, Melanotan I (afamelanotide) 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 I (afamelanotide).

  4. 04LabNot a test of Melanotan I (afamelanotide) aloneOther designMechanism

    The amino terminus of NDP-MSH appeared adjacent to a series of hydrophilic residues, with novel interactions at Cys196 (TM5) and Asp189 (extracellular loop 2) of MC4R.

    In plain wordsIn lab tests, the start of the NDP-MSH peptide sat next to several MC4R receptor residues and touched two new spots.

    Peptide
    Melanotan I (afamelanotide)
    Outcome
    Not applicableInteractions of the NDP-MSH amino terminus with MC4R
    Study

    humann: not reported in source

    Mutant human MC4R with cysteine substitutions (covalent attachment approach)
    Outcome group
    Receptor activity and mechanism · Pharmacology

    Source sentences

    Summary
    The amino-terminus appears to be adjacent to a series of hydrophilic residues with novel interactions at Cys196 (TM5) and Asp189 (extracellular loop 2).
    1 context sentence
    Summary · context
    This investigation utilized the covalent attachment approach to identify receptor residues in close proximity to the bound ligand [Nle(4),D-Phe(7)]melanocyte-stimulating hormone (NDP-MSH), thereby differentiating between residues directly involved in ligand binding and those mutations that compromise ligand binding by inducing conformational changes in the receptor.

    In this study, Melanotan I (afamelanotide) 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 I (afamelanotide).

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.

  1. Version 2Current

    13 Oct 2026, 21:44 UTC

    Study results updated

  2. Version 1

    13 Oct 2026, 16:31 UTC

    First added · source update from Europe PMC

Subjects

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