Cryo-EM structure of parathyroid hormone receptor type 1 in complex with a long-acting parathyroid hormone analog and G protein
Cryo-EM structure of parathyroid hormone receptor type 1 in complex with a long-acting parathyroid hormone analog and G protein
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DOI：
10.2210/pdb6nbf/pdb
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发表时间：
2019-04
期刊：
影响因子：
56.9
通讯作者：
Lihua Zhao;S. Ma;Ieva Sutkeviciute;D.-D. Shen-D.;X. E. Zhou;P. Waal;Chuankui Li;Yanyong Kang;Lisa J. Clark;F. Jean-Alphonse;A. White;Dongyong Yang;A. Dai;X. Cai;Jianmin Chen;Chun Xing Li;Y. Jiang;Tomoyuki Watanabe;T. Gardella;K. Melcher;Ming-Wei Wang;J. Vilardaga;H. E. Xu;Yan Zhang
中科院分区：
文献类型：
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作者：
Lihua Zhao;S. Ma;Ieva Sutkeviciute;D.-D. Shen-D.;X. E. Zhou;P. Waal;Chuankui Li;Yanyong Kang;Lisa J. Clark;F. Jean-Alphonse;A. White;Dongyong Yang;A. Dai;X. Cai;Jianmin Chen;Chun Xing Li;Y. Jiang;Tomoyuki Watanabe;T. Gardella;K. Melcher;Ming-Wei Wang;J. Vilardaga;H. E. Xu;Yan Zhang
甲状旁腺激素受体-1 （PTH1R）是一种B类G蛋白偶联受体，对钙稳态至关重要，是骨质疏松症和甲状旁腺功能减退症的治疗靶点。在这里，我们报道了人类PTH1R与长效PTH类似物和刺激G蛋白结合的低温电镜结构。结合肽采用延伸螺旋结构，其氨基末端深深插入受体跨膜结构域（TMD），导致跨膜螺旋6的羧基末端部分解绕，并在该螺旋中间诱导一个尖锐的扭结，使受体与G蛋白偶联。与单一的TMD结构状态相反，胞外结构域具有多种构象。这些结果为PTH结合和受体激活的结构基础和动力学提供了见解。
The parathyroid hormone receptor-1 (PTH1R) is a class B G protein–coupled receptor central to calcium homeostasis and a therapeutic target for osteoporosis and hypoparathyroidism. Here we report the cryo–electron microscopy structure of human PTH1R bound to a long-acting PTH analog and the stimulatory G protein. The bound peptide adopts an extended helix with its amino terminus inserted deeply into the receptor transmembrane domain (TMD), which leads to partial unwinding of the carboxyl terminus of transmembrane helix 6 and induces a sharp kink at the middle of this helix to allow the receptor to couple with G protein. In contrast to a single TMD structure state, the extracellular domain adopts multiple conformations. These results provide insights into the structural basis and dynamics of PTH binding and receptor activation.