在第11至13位修饰的氨基末端甲状旁腺激素相关肽的特性

Properties of amino-terminal parathyroid hormone-related peptides modified at positions 11-13.

作者信息

Jüppner H, Abou-Samra A B, Uneno S, Schipani E, Keutmann H T, Potts J T, Segre G V

机构信息

Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston 02114.

出版信息

Peptides. 1990 Nov-Dec;11(6):1139-42. doi: 10.1016/0196-9781(90)90143-s.

DOI:10.1016/0196-9781(90)90143-s

PMID:1965028

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 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.

摘要

使用ROS 17/2.8细胞检测了在11 - 13区域修饰的氨基末端PTHrP类似物的生物学特性。[亮氨酸11，D - 色氨酸12，精氨酸13，酪氨酸36]PTHrP(1 - 36)酰胺与受体的结合亲和力比[酪氨酸36]PTHrP(1 - 36)酰胺或[精氨酸11,13，酪氨酸36]PTHrP(1 - 36)酰胺低17倍（表观Kd：5×10(-8) M）（后两者的表观Kd均为：2×10(-9) M）。此外，尽管它能完全抑制放射性配体结合，但它只是一种弱部分激动剂。[亮氨酸11，D - 色氨酸12，精氨酸13，酪氨酸36，半胱氨酸38]PTHrP(7 - 38)和PTHrP(7 - 34)酰胺具有相似的受体亲和力（表观Kd：5×10(-8) M和8×10(-8) M），而[Nle8,18，酪氨酸34]bPTH(7 - 34)酰胺的受体亲和力则低10倍以上（表观Kd：2×10(-6) M）。这些生物学特性的变化表明，高亲和力受体结合需要PTHrP(1 - 36)序列的氨基末端和羧基末端结构域以及/或者分子内相互作用，而D - 色氨酸取代甘氨酸12会损害这些相互作用。