A molecular model that may provide a new framework for improving the design of osteoporosis treatments was developed using advanced mass spectrometry technology. The study was conducted by a research team from the Florida campus of The Scripps Research Institute (TSRI) and the findings are published in the journal Nature Communications. "Because of our aging population, these kinds of therapeutics are in great demand," said study leader Patrick R. Griffin, co-chair of the TSRI Department of Molecular Medicine. Using a technology known as HDX, which the Griffin lab has propelled into mainstream protein analysis, the scientists delivered the first dynamic snapshots of a prime target for osteoporosis treatments: a receptor that regulates calcium levels to maintain healthy bones.
‘HDX can show the specific regions of the protein complex that are altered on interaction with specific ligands, in this case the vitamin D receptor complex.’The use of current drugs that target this receptor--called vitamin D receptor agonists--is limited because use can result in hypercalcemia, a condition that can weaken bones and even cause kidney stones, due to too much calcium in the bloodstream.
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To address this problem, scientists need a clearer picture of the structure of the vitamin D receptor. The vitamin D receptor complex regulates bone mineralization by controlling a gene known as BGLAP that is the target of 1£\, 25-dihydroxyvitamin D3 (1,25D3), the active hormonal version of vitamin D. Unfortunately, increased levels of 1,25D3 also activate a calcium-regulating gene called TRPV6, which leads to hypercalcemia.
Griffin and his colleagues hope to eliminate this threat by developing 1,25D3 analogs (known as dissociated vitamin D receptor ligands or VDRMs) that differentially target BGLAP genes, while avoiding TRPV6.
"The idea is that if we could fingerprint how these various ligands interact with the vitamin D receptor, we could provide a kind of roadmap to help develop those that only trigger the non-hypercalcemia gene," Griffin said.
Until now, developing more selective compounds has been hampered by the fact that no one understood the structural mechanism that makes them work.
Griffin and his colleagues performed a detailed comparative biophysical study on hundreds of compounds, all with distinct chemical structures.
The scientists used hydrogen-deuterium exchange (HDX) mass spectrometry, a high-precision, high-sensitivity mapping technique that has proven to be a robust method to probe protein conformational or shape changing dynamics within the context of ligand and protein/protein interactions.
HDX can show the specific regions of the protein complex that are altered on interaction with specific ligands, in this case the vitamin D receptor complex, information which can be used to infer structural changes that are the result of a specific interaction.