Properties of amino-terminal parathyroid hormone-related peptides modified at positions 11-13.
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 x 10(-8) M) than [Tyr36]PTHrP(1-36)amide or [Arg11,13,Tyr36]PTHrP(1-36)amide (apparent Kd for both: 2 x 10(-9) M). Moreover, it is only a weak partial agonist despite completely inhibiting radioligand binding. [Leu11,D-Trp12,Arg13,Tyr36,Cys38]PTHrP(7-3 8) and PTHrP(7-34)amide had similar receptor affinities (apparent Kds: 5 x 10(-8) M and 8 x 10(-8) M), while that of [Nle8,18,Tyr34]bPTH(7-34)amide was more than 10-fold lower (apparent Kd: 2 x 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.
Jüppner
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Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston 02114.
Abou-Samra
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AB
Uneno
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Schipani
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E
Keutmann
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Potts
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JT
Segre
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GV
D000595:Amino Acid Sequence; D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis; D008969:Molecular Sequence Data; D010281:Parathyroid Hormone / Q000378:metabolism*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000378:metabolism*; D011869:Radioligand Assay; D011956:Receptors, Cell Surface / Q000378:metabolism; D018016:Receptors, Parathyroid Hormone; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D010281:Parathyroid Hormone; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D018016:Receptors, Parathyroid Hormone; D000242:Cyclic AMP