Ghrelin receptor inverse agonists: identification of an active peptide core and its interaction epitopes on the receptor

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

Ghrelin receptor inverse agonists: identification of an active peptide core and its interaction epitopes on the receptor. / Holst, Birgitte; Lang, Manja; Brandt, Erik; Bach, Anders; Howard, Andrew; Frimurer, Thomas M; Beck-Sickinger, Annette; Schwartz, Thue W.

In: Molecular Pharmacology, Vol. 70, No. 3, 2006, p. 936-46.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Holst, B, Lang, M, Brandt, E, Bach, A, Howard, A, Frimurer, TM, Beck-Sickinger, A & Schwartz, TW 2006, 'Ghrelin receptor inverse agonists: identification of an active peptide core and its interaction epitopes on the receptor', Molecular Pharmacology, vol. 70, no. 3, pp. 936-46. https://doi.org/10.1124/mol.106.024422

APA

Holst, B., Lang, M., Brandt, E., Bach, A., Howard, A., Frimurer, T. M., Beck-Sickinger, A., & Schwartz, T. W. (2006). Ghrelin receptor inverse agonists: identification of an active peptide core and its interaction epitopes on the receptor. Molecular Pharmacology, 70(3), 936-46. https://doi.org/10.1124/mol.106.024422

Vancouver

Holst B, Lang M, Brandt E, Bach A, Howard A, Frimurer TM et al. Ghrelin receptor inverse agonists: identification of an active peptide core and its interaction epitopes on the receptor. Molecular Pharmacology. 2006;70(3):936-46. https://doi.org/10.1124/mol.106.024422

Author

Holst, Birgitte ; Lang, Manja ; Brandt, Erik ; Bach, Anders ; Howard, Andrew ; Frimurer, Thomas M ; Beck-Sickinger, Annette ; Schwartz, Thue W. / Ghrelin receptor inverse agonists: identification of an active peptide core and its interaction epitopes on the receptor. In: Molecular Pharmacology. 2006 ; Vol. 70, No. 3. pp. 936-46.

Bibtex

@article{21c223e0f2fa11ddbf70000ea68e967b,
title = "Ghrelin receptor inverse agonists: identification of an active peptide core and its interaction epitopes on the receptor",
abstract = "[D-Arg1,D-Phe5,D-Trp7,9,Leu11]Substance P functions as a low-potency antagonist but a high-potency full inverse agonist on the ghrelin receptor. Through a systematic deletion and substitution analysis of this peptide, the C-terminal carboxyamidated pentapeptide wFwLX was identified as the core structure, which itself displayed relatively low inverse agonist potency. Mutational analysis at 17 selected positions in the main ligand-binding crevice of the ghrelin receptor demonstrated that ghrelin apparently interacts only with residues in the middle part of the pocket [i.e., between transmembrane (TM)-III, TM-VI and TM-VII]. In contrast, the inverse agonist peptides bind in a pocket that extends all the way from the extracellular end of TM-II (AspII:20) across between TM-III and TM-VI/VII to TM-V and TM-IV. The potency of the main inverse agonist could be improved up to 20-fold by a number of space-generating mutants located relatively deep in the binding pocket at key positions in TM-III, TM-IV and TM-V. It is proposed that the inverse agonists prevent the spontaneous receptor activation by inserting relatively deeply across the main ligand-binding pocket and sterically blocking the movement of TM-VI and TM-VII into their inward-bend, active conformation. The combined structure-functional analysis of both the ligand and the receptor allowed for the design of a novel, N-terminally Lys-extended analog of wFwLL, which rescued the high-potency, selective inverse agonism that was dependent upon both AspII:20 and GluIII:09. The identified pharmacophore can possibly serve as the basis for targeted discovery of also nonpeptide inverse agonists for the ghrelin receptor.",
author = "Birgitte Holst and Manja Lang and Erik Brandt and Anders Bach and Andrew Howard and Frimurer, {Thomas M} and Annette Beck-Sickinger and Schwartz, {Thue W}",
note = "Keywords: Amino Acid Sequence; Amino Acid Substitution; Animals; Binding Sites; COS Cells; Cells, Cultured; Cercopithecus aethiops; Epitopes; Ghrelin; Humans; Ligands; Models, Molecular; Molecular Sequence Data; Mutant Proteins; Peptide Hormones; Peptides; Protein Binding; Receptors, G-Protein-Coupled; Receptors, Ghrelin; Structure-Activity Relationship; Substance P",
year = "2006",
doi = "10.1124/mol.106.024422",
language = "English",
volume = "70",
pages = "936--46",
journal = "Molecular Pharmacology",
issn = "0026-895X",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",

}

RIS

TY - JOUR

T1 - Ghrelin receptor inverse agonists: identification of an active peptide core and its interaction epitopes on the receptor

AU - Holst, Birgitte

AU - Lang, Manja

AU - Brandt, Erik

AU - Bach, Anders

AU - Howard, Andrew

AU - Frimurer, Thomas M

AU - Beck-Sickinger, Annette

AU - Schwartz, Thue W

N1 - Keywords: Amino Acid Sequence; Amino Acid Substitution; Animals; Binding Sites; COS Cells; Cells, Cultured; Cercopithecus aethiops; Epitopes; Ghrelin; Humans; Ligands; Models, Molecular; Molecular Sequence Data; Mutant Proteins; Peptide Hormones; Peptides; Protein Binding; Receptors, G-Protein-Coupled; Receptors, Ghrelin; Structure-Activity Relationship; Substance P

PY - 2006

Y1 - 2006

N2 - [D-Arg1,D-Phe5,D-Trp7,9,Leu11]Substance P functions as a low-potency antagonist but a high-potency full inverse agonist on the ghrelin receptor. Through a systematic deletion and substitution analysis of this peptide, the C-terminal carboxyamidated pentapeptide wFwLX was identified as the core structure, which itself displayed relatively low inverse agonist potency. Mutational analysis at 17 selected positions in the main ligand-binding crevice of the ghrelin receptor demonstrated that ghrelin apparently interacts only with residues in the middle part of the pocket [i.e., between transmembrane (TM)-III, TM-VI and TM-VII]. In contrast, the inverse agonist peptides bind in a pocket that extends all the way from the extracellular end of TM-II (AspII:20) across between TM-III and TM-VI/VII to TM-V and TM-IV. The potency of the main inverse agonist could be improved up to 20-fold by a number of space-generating mutants located relatively deep in the binding pocket at key positions in TM-III, TM-IV and TM-V. It is proposed that the inverse agonists prevent the spontaneous receptor activation by inserting relatively deeply across the main ligand-binding pocket and sterically blocking the movement of TM-VI and TM-VII into their inward-bend, active conformation. The combined structure-functional analysis of both the ligand and the receptor allowed for the design of a novel, N-terminally Lys-extended analog of wFwLL, which rescued the high-potency, selective inverse agonism that was dependent upon both AspII:20 and GluIII:09. The identified pharmacophore can possibly serve as the basis for targeted discovery of also nonpeptide inverse agonists for the ghrelin receptor.

AB - [D-Arg1,D-Phe5,D-Trp7,9,Leu11]Substance P functions as a low-potency antagonist but a high-potency full inverse agonist on the ghrelin receptor. Through a systematic deletion and substitution analysis of this peptide, the C-terminal carboxyamidated pentapeptide wFwLX was identified as the core structure, which itself displayed relatively low inverse agonist potency. Mutational analysis at 17 selected positions in the main ligand-binding crevice of the ghrelin receptor demonstrated that ghrelin apparently interacts only with residues in the middle part of the pocket [i.e., between transmembrane (TM)-III, TM-VI and TM-VII]. In contrast, the inverse agonist peptides bind in a pocket that extends all the way from the extracellular end of TM-II (AspII:20) across between TM-III and TM-VI/VII to TM-V and TM-IV. The potency of the main inverse agonist could be improved up to 20-fold by a number of space-generating mutants located relatively deep in the binding pocket at key positions in TM-III, TM-IV and TM-V. It is proposed that the inverse agonists prevent the spontaneous receptor activation by inserting relatively deeply across the main ligand-binding pocket and sterically blocking the movement of TM-VI and TM-VII into their inward-bend, active conformation. The combined structure-functional analysis of both the ligand and the receptor allowed for the design of a novel, N-terminally Lys-extended analog of wFwLL, which rescued the high-potency, selective inverse agonism that was dependent upon both AspII:20 and GluIII:09. The identified pharmacophore can possibly serve as the basis for targeted discovery of also nonpeptide inverse agonists for the ghrelin receptor.

U2 - 10.1124/mol.106.024422

DO - 10.1124/mol.106.024422

M3 - Journal article

C2 - 16798937

VL - 70

SP - 936

EP - 946

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 3

ER -

ID: 10150085