Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Holst, B. et al.

Holst, Lang, Brandt, Bach, Howard, Frimurer, Beck-Sickinger, Schwartz,

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

[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.[1]

References

Ghrelin receptor inverse agonists: identification of an active peptide core and its interaction epitopes on the receptor. Holst, B., Lang, M., Brandt, E., Bach, A., Howard, A., Frimurer, T.M., Beck-Sickinger, A., Schwartz, T.W. Mol. Pharmacol. (2006) [Pubmed]

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