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Properties of amino-terminal parathyroid hormone-related peptides modified at positions 11–13 |
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| Authors: | Harald Jü ppner, Abdul-Badi Abou-Samra, Susumu Uneno, Ernestina Schipani, Henry T. Keutmann, John T. Potts Jr.,Gino V. Segre |
| Affiliation: | a Endocrine Unit, Department of Medicine, Massachusetts General Hospital Harvard Medical School, Fruit Street, Boston, MA 02114, USA b Department of Pediatrics, Massachusetts General Hospital Harvard Medical School, Fruit Street, Boston, MA 02114, USA |
| Abstract: | Biological properties of amino-terminal PTHrP analogues modified in the region 11–13 were examined using ROS 17/2.8 cells. [Leu11,D-Trp12,Arg13,Tyr36]PTHrP(1–36)amide had a 17-fold lower binding affinity for the receptor (apparent Kd: 5 × 10−8 M) than [Tyr36]PTHrP(1–36)amide or [Arg11,13,Tyr36]PTHrP(1–36)amide (apparent Kd for both: 2 × 10−9 M). Moreover, it is only a weak partial agonist despite completely inhibiting radioligand binding. [Leu11,D-Trp12,Arg13,Tyr36,Cys38]PTHrP(7–38) and PTHrP(7–34)amide had similar receptor affinities (apparent Kds: 5 × 10−8 M and 8 × 10−8 M), while that of [Nle8,18,Tyr34]bPTH(7–34)amide was more than 10-fold lower (apparent Kd: 2 × 10−6 M). These changes in biological properties suggest that high affinity receptor binding requires both amino- and carboxyl-terminal domains of the PTHrP(1–36) sequence and/or intramolecular interactions which are impaired by the D-Trp substitution for Gly12. |
| Keywords: | Parathyroid hormone (PTH) PTH-related peptide (PTHrP) Synthetic PTHrP analogues D-Trp substitution Partial agonist activity Receptor affinity ROS 17/2.8 cells |
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