Sci. Aging Knowl. Environ., 20 February 2002
Flipping Out: Crystal structure reveals how nuclear receptors turn on and off (Hormones; Nuclear receptors)
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/7/nw20
Key Words: PPAR SMRT nuclear receptor hormone
Abstract: As Olympic luger Georg Hackl hurtled down the Utah track on his way to a record fifth medal, a subtle twist of his foot steered the sled left or right. A similarly subtle adjustment in a protein turns a molecular switch off and on, according to new work. The study provides visual confirmation of a mechanism suspected to underlie the shifty behavior of nuclear receptors, a family of proteins that enable hormones and other small molecules to influence physiology. The results might lay the groundwork for new therapeutic strategies.
Nuclear receptor systems are crucial for many animals. When these systems go awry, cancer, obesity, diabetes, and other diseases can result. In the absence of a hormone, nuclear receptors attach to proteins termed corepressors. The pair binds to specific DNA sequences and turns genes off. Hormones, in contrast, render nuclear receptors able to grab proteins known as coactivators. This amalgam can instead turn genes on.
To investigate the structural changes that define the nuclear receptors' two dispositions, Xu and colleagues wanted to compare a nuclear receptor in both states. The team had previously generated a three-dimensional picture of the union between the nuclear receptor PPAR--a protein that controls the breakdown of fatty acids and the concentration of lipids in the bloodstream--and a corepressor. But the PPAR-corepressor pair eluded study because it broke apart easily. To overcome this obstacle, the group enlisted the help of an inhibitor of PPAR that stabilizes the union of the nuclear receptor with its corepressor. By shining x-rays through crystals of the trio and analyzing how the waves bent, the researchers deduced the position of each atom in the conglomeration of PPAR, corepressor, and inhibitor.
The team then inspected how the coactivator and the corepressor attached to PPAR. Both bind by laying a helical stretch of amino acids into a groove on the nuclear receptor. Most of PPAR's amino acids assume the same position regardless of its protein partner, but when the corepressor is bound, a small region of PPAR flips 90°. That shift lengthens PPAR's groove to accommodate the corepressor, whose binding helix is half again as long as that of the coactivator. The inhibitor appears to keep the nuclear receptor in the more open state, thereby encouraging corepressor binding.
Scientists had originally expected that corepressors and coactivators would bind to different regions of a nuclear receptor, but several biochemical studies published in 1999 suggested that they instead affix to the same spot. The new study bears out those predictions by furnishing a molecular snapshot and provides a more detailed view of the interactions, says biochemist Mitch Lazar of the University of Pennsylvania in Philadelphia. That additional understanding could help researchers create drugs that combat a wide range of hormone-related disorders. Like redirecting runners on a sled, they could use such compounds to send the system in one direction or the other, turning nuclear receptors on or off at will.
--R. John Davenport
Citation: R. J. Davenport, Flipping Out: Crystal structure reveals how nuclear receptors turn on and off (Hormones; Nuclear receptors). Science's SAGE KE (20 February 2002), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/7/nw20
Science of Aging Knowledge Environment. ISSN 1539-6150