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IN THIS ISSUE . . .
May 17, 2005
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The National Institute of General Medical Sciences (NIGMS), one of the National Institutes of Health, supports all research featured in this digest. Although only the lead scientists are named, coworkers and other collaborators also contributed to the findings. Additional items are posted at http://www.nigms.nih.gov/news/releases/funded_research.html.
Cool Image: Canine Kidney Cells Aglow
Cells from a dog's kidney light up green when a fluorescent protein tags transporter proteins embedded in the cell membranes. Transporter proteins in the liver and kidney purge drugs and other chemicals from the body. Genetic variations in these proteins can change how a person responds to medications. Provided by Kathy Giacomini, a biologist at the University of California, San Francisco. From PNAS 100: 5902-7. Copyright 2003 National Academy of Sciences, U.S.A.
Modeling Resistance to Malaria Drugs
Malaria is an expert escape artist. The disease, which kills one child every 30 seconds, is caused by a parasite in mosquito saliva. The parasite is so shifty it has evaded almost every antimalarial drug invented to treat it. Now, a research team led by biochemist Bernard Trumpower at Dartmouth Medical School has modeled five genetic mutations that allow the parasite to resist drugs. The scientists are using yeast (a laboratory workhorse) and computer modeling to design drugs that the mutant parasite can’t escape.
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"Dr. Trumpower's group developed a very useful strategy in the fight against malaria. It now has in hand the tools to design a new generation of drugs to treat this disease."
-- Peter Preusch, NIGMS program director for biochemistry
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Caption: A mosquito, which transmits the malaria parasite, and four models showing how an anitimalarial drug loses potency. Courtesy of the American Society for Biochemistry and Molecular Biology.
Pathway Shields Organisms from Oxygen Damage
Plants turn energy from the sun into the fuel they need to carry out important cellular functions. But this process, known as photosynthesis, also generates a toxic substance called singlet oxygen that can destroy biological molecules. New research led by University of Wisconsin-Madison bacteriologist Timothy Donohue shows that a photosynthetic microbe uses a cellular pathway to turn on certain genes, shielding its cells from oxidative damage. Other organisms, including humans, most likely have a similar response mechanism. Finding ways to enhance this protective response could disarm similar oxygen molecules implicated in many debilitating human conditions, including heart disease and cancer.
Caption: Singlet oxygen is produced inside the photosynthetic membrane system (red circles) of cells from the bacterium Rhodobacter sphaeroides (green). This toxic form of oxygen, which is found in many organisms, can damage proteins, cause mutations, and lead to debilitating diseases. Courtesy of Pacific Northwest National Laboratory, U.S. Department of Energy.
Seeing the Structural Basis of Antibiotic Resistance
About half of the antibiotics currently used to treat infections bind to bacterial ribosomes—the molecular machines that make bacterial proteins—and block their activity. But just a slight mutation in ribosomal RNA can make bacteria resistant to many of these drugs. Yale University structural biologists Thomas Steitz and Peter Moore used X-ray crystallography to visualize exactly how a particular antibiotic binds to a mutated ribosome. Their observations reveal why the drug binds so poorly and why bacteria carrying this particular mutation are far less sensitive to the drug. Steitz and Moore are among the co-founders of a pharmaceutical company that is applying this finding and others to the development of new antibiotics.
Image caption: This depiction shows a ribosomal chemical group found in a number of antibiotic-resistant bacteria (represented by red mesh) interacting with the antibiotic erythromycin (represented by black mesh and the superimposed "ball and stick" model). This undesired interaction is the basis for some bacteria's resistance to erythromycin and other similar antibiotics.
Unfolding Brain Disease
Knotted up protein clumps are a hallmark of over 100 disorders such as Alzheimer’s and Parkinson’s diseases. Researchers know that these protein knots form in steps—pairs of misfolded proteins grow into mid-length clusters that then extend to form long, tangled fibrils—but they strongly disagree on their roles in causing brain disorders. Now physiologist Ian Parker and molecular biologist Charles Glabe of the University of California, Irvine, found that the mid-length protein clusters damage brain cell membranes, making them leaky. The finding offers evidence that these clusters play a part in the early stages of disorders related to misfolded proteins.
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