VAI Finding Could Lead To New Drugs For Anxiety, Depression - How CRF Precisely Binds To Its Receptor

Main Category: Depression
Also Included In: Anxiety / Stress;  Neurology / Neuroscience;  Psychology / Psychiatry
Article Date: 16 Oct 2008 - 3:00 PDT

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Researchers in the Laboratory of Structural Sciences at Van Andel Institute (VAI) have determined how the hormone corticotrophin releasing factor (CRF) precisely binds to its receptor. This detailed structural information can help drug developers design new drugs for anxiety, depression, and related disorders.

"There are a few drugs in development to treat anxiety, depression, and other conditions by targeting the cellular receptor that CRF binds to, but there are no drugs currently on the market," said VAI Distinguished Scientific Investigator Eric Xu, Ph.D., who published his laboratory's findings in The Journal of Biological Chemistry. "There is a lot of interest in this receptor as a drug target, and we are the first to determine the structural details necessary to develop an ideal drug."

CRF is a hormone and neurotransmitter secreted by the hypothalamus area of the brain and is involved in stress response. CRF has been associated with anxiety, depression, and related disorders. The hormone's receptor is a protein on the surface of a cell or in its interior that binds to the hormone, which allows the hormone to activate changes in the cell.

Using a technique known as X-ray crystallography, VAI researchers determined the molecular structure of the part of the CRF receptor that sticks outside of the cell and binds to CRF and other proteins in the same family. This detailed structural information can help drug developers engineer a drug that more perfectly fits to the receptor, making the drug more potent. Researchers determined the structure of the receptor in three different scenarios - one with nothing bound to the receptor, one with CRF bound to the receptor, and one that shows how the receptor binds to other proteins in the same family.

To determine the structure, researchers had to crystallize the hormone and receptor in these different scenarios, a process similar to letting salty water evaporate to form salt crystals but much more difficult. The lab used a unique method to do this that they recently developed to determine the structure of the parathyroid hormone (PTH) receptor, used to treat osteoporosis. PTH and CRF receptors are in the same family of proteins.

"There are many therapeutically important receptors in the same family as CRF and PTH," said Xu, "and there is a good chance we may be able to apply our crystallizing method to even more members of this family going forward."

Established by Jay and Betty Van Andel in 1996, Van Andel Institute is an independent research organization dedicated to preserving, enhancing and expanding the frontiers of medical science, and to achieving excellence in education by probing fundamental issues of education and the learning process.

http://www.vai.org

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