In a technical tour de force, a pair of NIH-supported research teams have independently solved the much-sought molecular structure of a protein complex whose function is paramount to cellular metabolism. Together, the results should help scientists better understand the way in which electron transfer--the basis for energy production in subcellular compartments called mitochondria--takes place inside the cell.
The researchers determined the structure of the cytochrome bc 1 complex, the central component of the electron transport chain of mitochondria--the cellular "power plant" organelles that convert the energy in sugars into ATP, a more universal energy currency useful to all cells. Work published in the July 4, 1997 issue of Science, by NIGMS grantee Dr. Chang-An Yu and coworkers at Oklahoma State University and Dr. Johann Deisenhofer and coworkers at the University of Texas Southwestern Medical Center at Dallas, set the stage by unraveling the partial X-ray crystallographic structure of cytochrome bc 1 , a massive complex consisting of nearly a dozen proteins nestled in the membranes of mitochondria.
Assembling protein crystals from beef heart tissue, the scientists provided interesting new information about the way the complex goes about its business of shuttling electrons to and fro in the mitochondrial membrane. For instance, the studies show a functionally integrated double molecule (called a dimer) that forms channels where the critical chemistry of the enzyme takes place and that appears to undergo a conformational change during electron transfer.
In work reported more recently, in the April 16 issue of Nature, NIGMS grantee Dr. Antony Crofts at the University of Illinois at Urbana and Dr. Ed Berry, Dr. Sung-Hou Kim and colleagues at the Lawrence Berkeley National Laboratory, University of California, Berkeley and the Lawrence Berkeley National Berkeley, have since built on Yu's results, obtaining a more complete three-dimensional map of cytochrome bc 1 , including the structures of two a critical pieces of the complex called the Rieske iron-sulfur protein and cytochrome c 1 . Together, the two groups' findings represent a particularly important feat scientifically because the structures of only three mammalian membrane proteins, which are notoriously difficult to crystallize, have been determined.
The new results are important in another way: They are the first observation of electron shuttling via large-scale movement of a protein domain in a complex involved in electron transfer. By comparing crystal structures of cytochrome bc 1 in the presence or absence of various inhibitor compounds, the team reached the startling conclusion that the Rieske iron-sulfur protein doesn't just change its shape as previously suspected, but instead an entire portion of the protein actually hops back and forth from one position to another within the mega-complex.
Eventually, knowledge of the structural mechanisms of action of this critical molecule should improve our understanding of--and perhaps our ability to treat--a host of human disorders. Partial defects in human cytochrome bc 1 are associated with a number of rare genetic diseases, including Fanconi syndrome, a kidney disorder. In addition, cytochrome bc 1 failure may play a role in many other diseases, including Parkinson's, Alzheimer's, Huntington's, and diabetes. The complex is also a major source of production of superoxide, a natural chemical which damages proteins and nucleic acids, and has been implicated in the aging process. Selective inhibitors of the cytochrome bc 1 enzyme family could serve as antibiotics, fungicides, insecticides, or herbicides.
This research was supported in part by the National Institute of General Medical Sciences (NIGMS), a component of the National Institutes of Health that supports basic biomedical research.
Xia D, Yu C-A, Kim H, Xia J-Z, Kachurin A, Zhang L, Yu L, Deisenhofer J. The crystal structure of the cytochrome bc 1 complex from bovine heart mitochondria. Science 1997;277:60-66.
Zhang Z, Huang L, Shulmeister VM, Chi Y-I, Kim KK, Hung L-W, Crofts AR, Berry EA, Kim S-H. Electron transfer by domain movement in cytochrome bc 1 . Nature 1998;392:677-84.
Reporters may call the NIGMS Office of Communications and Public Liaison at (301) 496-7301 to obtain the name of a scientist in the NIGMS Division of Pharmacology, Physiology, and Biological Chemistry who can comment on this work.
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8/9/2018 4:40 PM
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