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In this movie, the Dbr1 enzyme rotates 360 degrees. Partially inhibiting Dbr1 could represent a new way to treat most cases of amyotrophic lateral sclerosis (ALS), according to a new...
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SAN ANTONIO, Texas, U.S.A. (Sept. 10, 2014) — Investigators from the School of Medicine at The University of Texas Health Science Center at San Antonio have determined the first high-resolution structure of an enzyme that, if partially inhibited, could represent a new way to treat most cases of amyotrophic lateral sclerosis (ALS, also called Lou Gehrig's disease).
Dbr1 is the only enzyme known to break loops of ribonucleic acids (RNAs) called intron lariats. When Dbr1 activity is high, very few of these lariats remain in cells.
"This is relevant to ALS because another protein called TDP-43 aggregates to form clumps in motor neurons in 50 percent to 80 percent of all ALS cases," said senior author P. John Hart, Ph.D., professor of biochemistry and director of the X-ray Crystallography Core Laboratory at the UT Health Science Center San Antonio. "Decreasing Dbr1 activity will cause some of these lariats to remain and when TDP-43 binds these lariats, it is prevented from forming clumps in motor neurons."
ALS is characterized by death of motor neurons, resulting in progressive paralysis.
"This is the first picture of this enzyme to be obtained," Dr. Hart said. "We can see all the details, which will help us to develop small molecules (drugs) to inhibit Dbr1 activity."
The other lead investigators on the paper, published as a "Breakthrough Manuscript" in Nucleic Acids Research, are Masad Dahma, Ph.D., professor and chair of the Department of Chemistry at McGill University in Montreal, and Scott Stevens, Ph.D., associate professor of molecular genetics and microbiology at The University of Texas at Austin.
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Visuals: the image below in high resolution and a movie that rotates the Dbr1 enzyme 360 degrees
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The University of Texas Health Science Center at San Antonio, one of the country's leading health sciences universities, ranks in the top 3 percent of all institutions worldwide receiving National Institutes of Health funding. The university's schools of medicine, nursing, dentistry, health professions and graduate biomedical sciences have produced more than 29,000 graduates. The $765 million operating budget supports eight campuses in San Antonio, Laredo, Harlingen and Edinburg. For more information on the many ways "We make lives better®," visit http://www.uthscsa.edu.
Structure of enzyme seen as target for ALS drugs
2014-09-11
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