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J. Biol. Chem., Vol. 276, Issue 2, 931-936, January 12, 2001

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Common Requirements for Melanocortin-4 Receptor Selectivity of Structurally Unrelated Melanocortin Agonist and Endogenous Antagonist, Agouti Protein^*

Julia Oosterom, Keith M. Garner, Wijnand K. den Dekker, Wouter A. J. Nijenhuis, Willem Hendrik Gispen, J. Peter H. Burbach, Greg S. Barsh^§, and Roger A. H. Adan^¶

From the  Department of Medical Pharmacology, Rudolf Magnus Institute for Neurosciences, University Medical Center Utrecht, P. O. Box 85060, 3508 AB Utrecht, The Netherlands and the ^§ Howard Hughes Medical Institute, Beckman Center B271A, Stanford University School of Medicine, Stanford, California 94305-5323

The activity of melanocortin receptors (MCR) is regulated by melanocortin peptide agonists and by the endogenous antagonists, Agouti protein and AgRP (Agouti-related protein). To understand how the selectivity for these structurally unrelated agonists and antagonist is achieved, chimeric and mutants MC3R and MC4R were expressed in cell lines and pharmacologically analyzed. A region containing the third extracellular loop, EC3, of MC4R was essential for selective Agouti protein antagonism. In addition, this part of MC4R, when introduced in MC3R, conferred Agouti protein antagonism. Further mutational analysis of this region of MC4R demonstrated that Tyr²⁶⁸ was required for the selective interaction with Agouti protein, because a profound loss of the ability of Agouti protein to inhibit ¹²⁵I-labeled [Nle⁴,D-Phe⁷]-melanocyte-stimulating hormone (MSH) binding was observed by the single mutation of Tyr²⁶⁸ to Ile. This same residue conferred selectivity for the MC4R selective agonist, [D-Tyr⁴]MT-II, whereas it inhibited interaction with the MC3R-selective agonist, [Nle⁴]Lys-₂-MSH. Conversely, mutation of Ile²⁶⁵ in MC3 (the corresponding residue of Tyr²⁶⁸) to Tyr displayed a gain of affinity for [D-Tyr⁴]MT-II, but not for Agouti protein, and a loss of affinity for [Nle⁴]Lys-₂-MSH as compared with wild-type MC3R. This single amino acid mutation thus confers the selectivity of MC3R toward a pharmacological profile like that observed for MC4R agonists but not for the antagonist, Agouti protein. Thus, selectivity for structurally unrelated ligands with opposite activities is achieved in a similar manner for MC4R but not for MC3R.

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