Molecular determinants of human melanocortin-4 receptor responsible for antagonist SHU9119 selective activity.

The Journal of Biological Chemistry
Yingkui YangCarroll M Harmon

Abstract

The hypothalamic melanocortin-4 receptor (MC4R), a seven transmembrane G-protein-coupled receptor, plays an important role in the regulation of body weight. The synthetic melanocortin analog SHU9119 has been widely used to characterize the physiological role of MC4R in feeding behavior and energy homeostasis. Previous studies indicated that SHU9119 is an agonist at the melanocortin-1 receptor (MC1R) but an antagonist at the MC4R. However, the molecular basis of the interaction between hMC4R and SHU9119 has not been clearly defined. To gain insight into the molecular determinants of hMC4R in the selectivity of SHU9119 chimeras and mutants hMC1R and hMC4R were expressed in cell lines and pharmacologically analyzed. A region of receptor containing the third transmembrane of hMC4R was found to be required for selective SHU9119 antagonism. Further mutagenesis studies of this region of hMC4R demonstrated that the amino acid residue leucine 133 in the third transmembrane was critical for the selective antagonist activity of SHU9119. The single substitution of leucine 133 to methionine did not affect SHU9119 binding to hMC4R. However, this substitution did convert SHU9119 from an antagonist to an agonist. Conversely, exchange of Met(12...Continue Reading

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Citations

Aug 24, 2005·Biochemistry·Irina D PogozhevaHenry I Mosberg
Sep 12, 2009·Biochemistry·Yingkui YangCarroll M Harmon
Sep 28, 2012·Journal of Molecular Endocrinology·Xiu-Lei MoYa-Xiong Tao
Jun 10, 2011·European Journal of Medicinal Chemistry·Paolo GriecoAlfonso Carotenuto
Jan 7, 2011·European Journal of Pharmacology·Yingkui Yang
Jan 8, 2011·European Journal of Pharmacology·Benjamin J RenquistRoger D Cone
Jun 23, 2009·General and Comparative Endocrinology·E SánchezJ M Cerdá-Reverter
Jul 10, 2003·Annals of the New York Academy of Sciences·Jerry Ryan Holder, Carrie Haskell-Luevano
Jan 10, 2004·Journal of Neurochemistry·José Miguel Cerdá-ReverterRichard Ector Peter
Jul 6, 2006·Regulatory Peptides·Min ChenYingkui Yang
Mar 3, 2004·Medicinal Research Reviews·Jerry Ryan Holder, Carrie Haskell-Luevano
Oct 10, 2003·The Journal of Pharmacology and Experimental Therapeutics·Zhenhai GaoDavid Duhl
Feb 27, 2003·The Journal of Pharmacology and Experimental Therapeutics·Sarah A NickollsRichard A Maki
Jan 22, 2015·The Journal of Biological Chemistry·Yingkui YangCarroll M Harmon
Jul 10, 2003·Annals of the New York Academy of Sciences·Helgi B SchiöthRobert Fredriksson
Aug 14, 2020·International Journal of Molecular Sciences·Gunnar KleinauPatrick Scheerer
Oct 21, 2020·International Journal of Molecular Sciences·Li-Kun Yang, Ya-Xiong Tao

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