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.
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 PTH＇IR 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 （TM） domain, 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.
出处
《物理化学学报》
SCIE
CAS
CSCD
北大核心
2012年第7期1783-1789,共7页
Acta Physico-Chimica Sinica
