Inverse agonist activity of agouti and agouti-related protein |
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Authors: | Chai Biao-Xin Neubig Richard R Millhauser Glenn L Thompson Darren A Jackson Pilgrim J Barsh Gregory S Dickinson Chris J Li Ji-Yao Lai Yu-Mei Gantz Ira |
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Institution: | Department of Surgery, University of Michigan Medical Center, Ann Arbor 48109-0682, USA. |
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Abstract: | Agouti and agouti-related protein (AgRP) are endogenous antagonists of the melanocortin receptors (MCxR). Previous data showed that recombinant full-length agouti and a synthetic fragment of AgRP, AgRP (83-132), are inverse agonists at the MC1R and MC4R, respectively. This study demonstrates the smaller analogs AgRP (87-120) and ASIP 90-132 (L89Y)], and short peptides YcCRFFNAFC]Y and QcCRFFRSAC]S are also MC4R inverse agonists. Furthermore, the relative affinity of the series of MC4R ligands for displacement of radiolabeled antagonist 125I-AgRP (86-132) versus radiolabeled agonist 125I-NDP-MSH did not correlate with ligand efficacy, which is more consistent with an induced-fit model than a simple two-state model of MC4R activation. These data shed new light on the determinants and mechanism of inverse agonism at the MC4R. |
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