物理化学学报 >> 2012, Vol. 28 >> Issue (07): 1783-1789.doi: 10.3866/PKU.WHXB201204192

生物物理化学 上一篇    下一篇

人甲状腺旁素1型受体的结构特征

林克江, 朱冬吉, 冷勇敢, 尤启冬   

  1. 中国药科大学药物化学教研室, 南京 210009
  • 收稿日期:2012-02-22 修回日期:2012-04-19 发布日期:2012-06-07
  • 通讯作者: 尤启冬 E-mail:Youqd@163.com

Structural Characterization of Human Parathyroid Hormone 1 Receptor

LIN Ke-Jiang, ZHU Dong-Ji, LENG Yong-Gan, YOU Qi-Dong   

  1. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, P. R. China
  • Received:2012-02-22 Revised:2012-04-19 Published:2012-06-07
  • Contact: YOU Qi-Dong E-mail:Youqd@163.com

摘要:

人甲状腺旁素1 型受体(PTH1R)是骨形成相关的B类G蛋白偶联受体, 其底物甲状腺旁腺素(PTH)及类似物具有抗骨质疏松作用. 由于此类受体的三维结构难以进行实验测定, 本文采用同源模建的方法, 完整构建了胞外区、跨膜区及其它相关区域, 并通过对接研究, 阐明复合物的氢键、疏水性相互作用及其与底物的相互作用关系和关键位点. 为进一步设计和发展此类药物提供理论依据.

关键词: 甲状腺旁素1型受体, 甲状腺旁素, 同源模建, 甲状腺旁素复合物

Abstract:

Parathyroid hormone 1 receptor (PTH1R) is a member of the class B G-protein coupled receptor (B-GPCR) family and is involved in bone formation. Its substrate parathyroid hormone (PTH) and its analogues are being developed as anti-osteoporosis therapeutics. The structure-based rational drug design of PTH1R substrates has been hampered by the lack of experimentally determined three-dimensional (3D) structures from techniques such as nuclear magnetic resonance (NMR) and X-ray crystallography. Here, we have constructed a 3D model of PTH1R including its extracellular domain (ECD), transmembrane domain (TM) and other domains using a homology modeling approach. In addition, to capture the ligand-receptor interactions, we have manually docked human parathyroid hormone (1-34) into the top scoring receptor model, and subjected the PTH-PTH1R complex to an unconstrained energy minimization. The integral 3D receptor model provides an easier way to understand the interactions involved at the TM, ECD, and other domains. Furthermore, the parameters of hydrogen bonding, hydrophobic, and other interactions from the ligand-receptor model, enabled us to elucidate the important interactions between PTH (1-34) and PTH1R. This ligand-receptor model could potentially serve as a tool for structure-based virtual screening in the development of non-peptide based anti-osteoporosis drugs.

Key words: Parathyroid hormone 1 receptor, Parathyroid hormone, Homology modeling, PTH-PTH1R complex

MSC2000: 

  • O641