Citation: LIN Ke-Jiang, ZHU Dong-Ji, LENG Yong-Gan, YOU Qi-Dong. Structural Characterization of Human Parathyroid Hormone 1 Receptor[J]. Acta Physico-Chimica Sinica, ;2012, 28(07): 1783-1789. doi: 10.3866/PKU.WHXB201204192 shu

Structural Characterization of Human Parathyroid Hormone 1 Receptor

1.
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, P. R. China

Received Date: 22 February 2012
Available Online: 19 April 2012

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.
- Parathyroid hormone 1 receptor,
- Parathyroid hormone,
- Homology modeling,
- PTH-PTH1R complex
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