title: Binding Selectivity of Abaloparatide for PTH-Type-1-Receptor Conformations and Effects on Downstream Signaling.
abstract: The PTH receptor type 1 (PTHR1) mediates the actions of two endogenous polypeptide ligands, PTH and PTHrP, and thereby plays key roles in bone biology. Based on its capacity to stimulate bone formation, the peptide fragment PTH (1-34) is currently in use as therapy for osteoporosis. Abaloparatide (ABL) is a novel synthetic analog of human PTHrP (1-34) that holds promise as a new osteoporosis therapy, as studies in animals suggest that it can stimulate bone formation with less of the accompanying bone resorption and hypercalcemic effects that can occur with PTH (1-34). Recent studies in vitro suggest that certain PTH or PTHrP ligand analogs can distinguish between two high-affinity PTHR1 conformations, R(0) and RG, and that efficient binding to R(0) results in prolonged signaling responses in cells and prolonged calcemic responses in animals, whereas selective binding to RG results in more transient responses. As intermittent PTH ligand action is known to favor the bone-formation response, whereas continuous ligand action favors the net bone-resorption/calcemic response, we hypothesized that ABL binds more selectively to the RG vs the R(0) PTHR1 conformation than does PTH (1-34), and thus induces more transient signaling responses in cells. We show that ABL indeed binds with greater selectivity to the RG conformation than does PTH (1-34), and as a result of this RG bias, ABL mediates more transient cAMP responses in PTHR1-expressing cells. The findings provide a plausible mechanism (ie, transient signaling via RG-selective binding) that can help account for the favorable anabolic effects that ABL has on bone.
authors.affiliation: Radius Health Inc (G.H., H.B.), Waltham, Massachusetts 02451; and Endocrine Unit (T.D., B.A.C., T.J.G.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Gary
authors.initials: G
authors.lastname: Hattersley
authors.affiliation: Radius Health Inc (G.H., H.B.), Waltham, Massachusetts 02451; and Endocrine Unit (T.D., B.A.C., T.J.G.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dean
authors.affiliation: Radius Health Inc (G.H., H.B.), Waltham, Massachusetts 02451; and Endocrine Unit (T.D., B.A.C., T.J.G.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Braden A
authors.initials: BA
authors.lastname: Corbin
authors.affiliation: Radius Health Inc (G.H., H.B.), Waltham, Massachusetts 02451; and Endocrine Unit (T.D., B.A.C., T.J.G.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Hila
authors.initials: H
authors.lastname: Bahar
authors.affiliation: Radius Health Inc (G.H., H.B.), Waltham, Massachusetts 02451; and Endocrine Unit (T.D., B.A.C., T.J.G.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Gardella
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D017930:Genes, Reporter / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008958:Models, Molecular; D044162:Parathyroid Hormone-Related Protein / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects*
chemical_list: D050071:Bone Density Conservation Agents; D008024:Ligands; C473449:PTH1R protein, human; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D044168:Receptor, Parathyroid Hormone, Type 1; D011994:Recombinant Proteins; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C000596789:abaloparatide; D000242:Cyclic AMP; D019204:GTP-Binding Proteins