TY - JOUR
T1 - Current trends in the structure - Activity relationship studies of the endogenous agouti-related protein (AGRP) melanocortin receptor antagonist
AU - Wilczynski, Andrzej M.
AU - Joseph, Christine G.
AU - Haskell-Luevano, Carrie
PY - 2005/9
Y1 - 2005/9
N2 - Agouti-related protein (AGRP) is an endogenous antagonist of the melanocortin-3 and -4 (MC3R and MC4) G-protein coupled receptors. The 87-132 amino acid C-terminal domain of hAGRP possesses five disulfide bridges and a well-defined three-dimensional structure that displays full biological activity as compared to the full-length protein. Based on the NMR structure of the C-terminal AGRP(87-132), a novel mini-protein, referred to as "Mini-AGRP" was designed that exhibited receptor binding affinity and antagonism similar to that of the parent hAGRP(87-132) protein. It was demonstrated that this new-engineered protein autonomously folds to the inhibitor cystine knot (ICK) motif. As this AGRP is a novel mammalian protein involved in energy homeostasis and possibly other physiological functions remaining to be identified, structure-function studies are starting to emerge toward the understanding of how this unique protein putatively interacts with the melanocortin receptors with the objective of designing potential therapeutic agents for in vivo physiological studies. This article summarizes the progress to date of AGRP-based structure-activity relationships and putative ligand-receptor interactions.
AB - Agouti-related protein (AGRP) is an endogenous antagonist of the melanocortin-3 and -4 (MC3R and MC4) G-protein coupled receptors. The 87-132 amino acid C-terminal domain of hAGRP possesses five disulfide bridges and a well-defined three-dimensional structure that displays full biological activity as compared to the full-length protein. Based on the NMR structure of the C-terminal AGRP(87-132), a novel mini-protein, referred to as "Mini-AGRP" was designed that exhibited receptor binding affinity and antagonism similar to that of the parent hAGRP(87-132) protein. It was demonstrated that this new-engineered protein autonomously folds to the inhibitor cystine knot (ICK) motif. As this AGRP is a novel mammalian protein involved in energy homeostasis and possibly other physiological functions remaining to be identified, structure-function studies are starting to emerge toward the understanding of how this unique protein putatively interacts with the melanocortin receptors with the objective of designing potential therapeutic agents for in vivo physiological studies. This article summarizes the progress to date of AGRP-based structure-activity relationships and putative ligand-receptor interactions.
KW - AGRP
KW - G-protein coupled receptors
KW - ICK domain
KW - Melanocortin receptors
KW - Structure-activity relationship
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U2 - 10.1002/med.20037
DO - 10.1002/med.20037
M3 - Review article
C2 - 16044415
AN - SCOPUS:24144487679
SN - 0198-6325
VL - 25
SP - 545
EP - 556
JO - Medicinal Research Reviews
JF - Medicinal Research Reviews
IS - 5
ER -