title: Small Molecule Inhibited Parathyroid Hormone Mediated cAMP Response by N-Terminal Peptide Binding.
abstract: Ligand binding to certain classes of G protein coupled receptors (GPCRs) stimulates the rapid synthesis of cAMP through G protein. Human parathyroid hormone (PTH), a member of class B GPCRs, binds to its receptor via its N-terminal domain, thereby activating the pathway to this secondary messenger inside cells. Presently, GPCRs are the target of many pharmaceuticals however, these drugs target only a small fraction of structurally known GPCRs (about 10%). Coordination complexes are gaining interest due to their wide applications in the medicinal field. In the present studies we explored the potential of a coordination complex of Zn(II) and anthracenyl-terpyridine as a modulator of the parathyroid hormone response. Preferential interactions at the N-terminal domain of the peptide hormone were manifested by suppressed cAMP generation inside the cells. These observations contribute a regulatory component to the current GPCR-cAMP paradigm, where not the receptor itself, but the activating hormone is a target. To our knowledge, this is the first report about a coordination complex modulating GPCR activity at the level of deactivating its agonist. Developing such molecules might help in the control of pathogenic PTH function such as hyperparathyroidism, where control of excess hormonal activity is essentially required.
authors.affiliation: Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK.|Institute of Physics, Biophysics, Martin-Luther-University Halle-Wittenberg, Germany.
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Institute of Physics, Biophysics, Martin-Luther-University Halle-Wittenberg, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Baumann
authors.affiliation: Institute of Physics, Biophysics, Martin-Luther-University Halle-Wittenberg, Germany.|Centre for Structure und Dynamics of Proteins (MZP), Martin-Luther-University Halle-Wittenberg, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Balbach
mesh_terms: D002942:Circular Dichroism; D000242:Cyclic AMP / Q000378:metabolism*; D006801:Humans; D019906:Nuclear Magnetic Resonance, Biomolecular; D010281:Parathyroid Hormone / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D010455:Peptides / Q000378:metabolism*; D011485:Protein Binding; D013050:Spectrometry, Fluorescence; D013816:Thermodynamics
chemical_list: C470125:PTH protein, human; D010281:Parathyroid Hormone; D010455:Peptides; D000242:Cyclic AMP