Molecular mechanism of agonism and inverse agonism in the melanocortin receptors: Zn(2+) as a structural and functional probe

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Among the rhodopsin-like 7TM receptors, the MC receptors are functionally unique because their high constitutive signaling activity is regulated not only by endogenous peptide agonists-MSH peptides-but also by endogenous inverse agonists, namely, the proteins agouti and AGRP. Moreover, the metal-ion Zn(2+) increases the signaling activity of at least the MC1 and MC4 receptors in three distinct ways: (1). by directly functioning as an agonist; (2). by potentiating the action of the endogenous agonist; and (3). by inhibiting the binding of the endogenous inverse agonist. Structurally the MC receptors are part of a small subset of 7TM receptors in which the main ligand-binding crevice, and especially extracellular loops 2 and 3, appear to be specially designed for easy ligand access and bias towards an active state of the receptor-i.e., constitutive activity. Thus, in the MC receptors extracellular loop 2 is ultrashort because TM-IV basically connects directly into TM-V, whereas extracellular loop 3 appears to be held in a particular, constrained conformation by a putative, internal disulfide bridge. The interaction mode for the small and well-defined zinc-ion between a third, free Cys residue in extracellular loop 3 and conceivably an Asp residue located at the inner face of TM-III gives important information concerning the activation mechanism for the MC receptors.
Original languageEnglish
JournalAnnals of the New York Academy of Sciences
Pages (from-to)1-11
Number of pages10
Publication statusPublished - 2003

Bibliographical note

Keywords: Animals; Binding Sites; Humans; Ligands; Melanocyte-Stimulating Hormones; Models, Molecular; Molecular Structure; Protein Structure, Secondary; Protein Structure, Tertiary; Receptors, Corticotropin; Receptors, Melanocortin; Rhodopsin; Signal Transduction; Zinc

ID: 10536435