...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Endocrinology >A monoclonal antibody with thyrotropin (TSH) receptor inverse agonist and TSH antagonist activities binds to the receptor hinge region as well as to the leucine-rich domain.
【24h】

A monoclonal antibody with thyrotropin (TSH) receptor inverse agonist and TSH antagonist activities binds to the receptor hinge region as well as to the leucine-rich domain.

机译：具有促甲状腺激素（TSH）受体反向激动剂和TSH拮抗剂活性的单克隆抗体与受体铰链区以及富亮氨酸结构域结合。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Monoclonal antibody CS-17 is a TSH receptor (TSHR) inverse agonist (suppresses constitutive activity) and a TSH antagonist. Elucidation of the CS-17 epitope will provide insight into TSHR structure and function. Present information on its epitope conflicts with recent data regarding another TSHR inverse agonist antibody. To characterize further the CS-17 epitope, we exploited the observation that CS-17 does not recognize a chimeric receptor with TSHR hinge region residues 261-289 replaced with homologous rat LH receptor residues (13 mismatches). We generated individual and double TSHR mutations corresponding to these mismatches. On flow cytometry, only T273L/R274V reduced CS-17 recognition. No mutation affected TSH-stimulated cAMP generation. Because the immunogen for CS-17 generation was highly glycosylated, we also investigated whether the glycan moiety at N198, topologically adjacent to Y195 (a previously identified epitopic component), could contribute to the CS-17 epitope. Elimination of this N-linked glycan (mutations of N198 and T200) abrogated CS-17 binding without altering TSH responsiveness. However, studies with tunicamycin suggested that these mutations affected CS-17 binding by altering the polypeptide backbone rather than eliminating the glycan moiety. TSHR residues N198 and T200, like Y195, are on the convex facet of the leucine-rich domain. In summary, the present data indicate that the discontinuous epitope of CS-17, a TSHR inverse agonist and TSH antagonist, includes a component in the hinge region as well as the convex surface of the TSHR leucine-rich domain. These findings expand our present concept of glycoprotein hormone binding and function.
机译：单克隆抗体CS-17是TSH受体（TSHR）反向激动剂（抑制组成型活性）和TSH拮抗剂。对CS-17表位的阐明将提供对TSHR结构和功能的了解。有关其表位的当前信息与有关另一种TSHR反向激动剂抗体的最新数据相冲突。为了进一步表征CS-17表位，我们利用CS-17无法识别TSHR铰链区残基261-289被同源大鼠LH受体残基（13个错配）取代的嵌合受体的观察。我们生成了与这些错配相对应的单个和双重TSHR突变​​。在流式细胞仪上，只有T273L / R274V降低了CS-17的识别率。没有突变影响TSH刺激的cAMP生成。因为CS-17世代的免疫原高度糖基化，所以我们还研究了拓扑结构上与Y195（先前确定的表位成分）相邻的N198处的聚糖部分是否可导致CS-17表位。消除这种N-连接的聚糖（N198和T200的突变）可消除CS-17的结合，而不会改变TSH的响应性。但是，衣霉素的研究表明，这些突变通过改变多肽主链而不是消除聚糖部分而影响了CS-17的结合。 TSHR残基N198和T200（如Y195）在富含亮氨酸的结构域的凸面上。总而言之，本数据表明，TSHR反向激动剂和TSH拮抗剂CS-17的不连续表位包括铰链区以及富含TSHR亮氨酸的结构域的凸表面。这些发现扩展了我们目前糖蛋白激素结合和功能的概念。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号