Full atomic simulation of the parathyroid hormone/ parathyroid hormone-related protein type 1 receptor ligand binding

Parathyroid hormone/ parathyroid hormone-related protein type 1 receptor, known as PTHR1, is a family of B class G protein couple receptors, its structure contains 7 α helix. PTHR1 regulates skeletal development, bone turnover and calcium ion concentration. Binding of PTHR1 and the ligand of Parathyroid hormone, PTH and Parathyroid hormone-related protein changes the conformations of PTHR1 and plays important role in transferring the signal for crucial biochemical reactions. However, the transmembrane domain structure of PTHR1.is still unclear. Only the structure of extracellular domain of PTHR1 has been revealed by the experiments. The conformation of the transmembrane domain of PTHR1 is known to be playing important role in the signaling mechanism. On the other hand, PTHR1 is associated with many diseases, such as Osteoporosis, Hypoparathyroidism, Brachydactyl type E and Eiken syndrome. Therefore understanding and developing the full atomistic and conformation of the full length PTHR1, can provide the new insights into these diseases and help the design of drugs. The transmembrane domains of Glucagon receptor and corticotropin-releasing factor receptor 1 have been revealed by the experiments. On account of the sequence similarities, we use the comparative protein structure modelling software, Modeller to predict the transmembrane structure of PTHR1. In this thesis, we combined the molecular dynamics and Modeller to solve the structure of full length PTHR1. The hydrogen bonds, hydrophobic interactions and the disulfide bonds are analyzed to provide fundamental insights into the structure and binding sites of the PTHR1 This study also provides a framework to study the structure of PTHR1 in membrane. In the future, we can use this model to investigate the ligand binding mechanisms of PTHR1, enabling the design of new treatments with the disease for PTHR1 related diseases.