Binding Selectivity of Abaloparatide for PTH-Type-1-Receptor Conformations and Effects on Downstream Signaling

Endocrinology. 2016 Jan;157(1):141-9. doi: 10.1210/en.2015-1726. Epub 2015 Nov 12.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites / drug effects
  • Bone Density Conservation Agents / chemistry
  • Bone Density Conservation Agents / metabolism*
  • Bone Density Conservation Agents / pharmacology
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cyclic AMP / metabolism*
  • GTP-Binding Proteins / metabolism*
  • Genes, Reporter / drug effects
  • Guanosine 5'-O-(3-Thiotriphosphate) / chemistry
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • HEK293 Cells
  • Humans
  • Kinetics
  • Ligands
  • MAP Kinase Signaling System / drug effects
  • Models, Molecular*
  • Parathyroid Hormone-Related Protein / chemistry
  • Parathyroid Hormone-Related Protein / metabolism*
  • Parathyroid Hormone-Related Protein / pharmacology
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology
  • Protein Conformation
  • Receptor, Parathyroid Hormone, Type 1 / chemistry
  • Receptor, Parathyroid Hormone, Type 1 / genetics
  • Receptor, Parathyroid Hormone, Type 1 / metabolism*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Second Messenger Systems / drug effects*


  • Bone Density Conservation Agents
  • Ligands
  • PTH1R protein, human
  • Parathyroid Hormone-Related Protein
  • Peptide Fragments
  • Receptor, Parathyroid Hormone, Type 1
  • Recombinant Proteins
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • abaloparatide
  • Cyclic AMP
  • GTP-Binding Proteins