Interactions of the Melanocortin-4 Receptor with the Peptide Agonist NDP-MSH |
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Authors: | Kathryn L Chapman Gemma K Kinsella Dan Donnelly |
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Institution: | 1 School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, UK 2 Department of Biology, National University of Ireland Maynooth, Maynooth, Co. Kildare, Ireland |
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Abstract: | 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 His6-Phe7-Arg8-Trp9, 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 Nle4,d-Phe7]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-Phe7 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 Trp9.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 β2-adrenergic receptor, with the former interaction being equivalent to the known interaction involving Ser204 of the β2-adrenergic receptor. |
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Keywords: | MC4R melanocortin-4 receptor NDP-MSH [Nle4 d-Phe7]melanocyte-stimulating hormone" target="_blank">d-Phe7]melanocyte-stimulating hormone TM transmembrane MCR melanocortin receptor GPCR G-protein-coupled receptor MSH melanocyte-stimulating hormone MTII melanotan II d-Nal" target="_blank">d-Nal d-alanine" target="_blank">β-(2-naphthyl)-d-alanine ECL extracellular loop hMC4R human MC4R PDB Protein Data Bank WT wild type CRE cyclic AMP response element CuP copper 1 10-phenanthroline MC1R melanocortin-1 receptor PDF probability density function |
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