Researchers have mapped in detail the molecular structure and dynamics of the cell receptor that “reads” the signals sent by the parathyroid hormone (PTH), which is defective in people with hypoparathyroidism.
The new insights may help develop more effective treatments with fewer side effects to modulate the activity of this receptor.
The study, “Structure and dynamics of the active human parathyroid hormone receptor-1,” was published in the journal Science.
Understanding in depth the shape of a protein helps scientists predict a number of important factors. It works as a blueprint of that protein’s role, its interaction with other proteins or factors, and its chemical properties.
One of its most important applications is for drug development. Knowing in detail a protein’s shape enables scientists to optimize the efficiency with which a compound binds to a target protein, activating or blocking its activity.
In this study, researchers were interested in unraveling with high resolution the structure of the parathyroid hormone receptor-1 (PTH1R), which works as an “antenna” at the surface of cells and to which the parathyroid hormone (PTH) and PTH-related peptide (PTHrP) bind. This receptor then transmits the signals received from PTH and PTHrP to other cells.
PTH and PTHrP are two hormones that play important roles in the body’s regulation of calcium levels, skeletal development, and bone turnover. Too many or too few of these hormones cause health issues that are sometimes life-threatening.
PTH deficiency is the underlying cause of hypoparathyroidism, typically resulting in abnormally low calcium levels in the body. But overly high levels can also be dangerous; in cancer patients, for instance. Some tumors can produce too much PTHrP, raising calcium to harmful levels, which can contribute to deadly cachexia (severe weakness and weight loss).
Thus, substances that mimic the action of both hormones, and activate or inhibit the receptor, have been developed as therapeutic agents for osteoporosis, and a recombinant (lab-made) PTH (brand name Natpara) is also approved as a replacement therapy for hypoparathyroidism.
Mapping in detail how these two molecules fit together with their receptor will likely provide important clues on how to modulate the receptor’s activity, which can be “important for the development of treatments for a number of diseases, including osteoporosis and cancer,” researchers said.
The team used cryo-electron microscopy — a method that has revolutionized the way scientists visualize the structure of large proteins, or complexes of different proteins — with a very high resolution.
Using this method, the team determined the shape of the PTH1R receptor — at near-atomic resolution — when bound to two key messengers: a long-acting PTH-like agent and a stimulatory G protein.
The latter couples to the receptor inside cells and plays a major role in mediating its messages in response to PTH, which in turns controls the breaking down of bone and regulates calcium levels.
Using 3D models of this interaction, researchers were able to determine the specific changes in shape that accompany the activation of the receptor in the presence of PTH. They also discovered the receptor could adopt multiple conformations.
“These results provide insights into the structural basis and dynamics of PTH binding and receptor activation,” the researchers stated.
The study also provides insights into G protein-coupled receptors (GPCRs), a family of signaling molecules to which PTH1R belongs, and targeted by many medications on the market.
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