Molecular mechanism of agonism and inverse agonism in the melanocortin receptors: Zn(2+) as a structural and functional probe.
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.
Holst
Birgitte
B
Laboratory for Molecular Pharmacology, The Panum Institute, University of Copenhagen, Denmark. b.holst@molpharm.dk
Schwartz
Thue W
TW
D000818:Animals; D001665:Binding Sites; D006801:Humans; D008024:Ligands; D009074:Melanocyte-Stimulating Hormones / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D018043:Receptors, Corticotropin / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D044101:Receptors, Melanocortin; D012243:Rhodopsin / Q000737:chemistry; D015398:Signal Transduction / Q000502:physiology*; D015032:Zinc / Q000378:metabolism*
D008024:Ligands; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; D009074:Melanocyte-Stimulating Hormones; D012243:Rhodopsin; D015032:Zinc