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Structural basis for the inhibition of human alkyladenine DNA glycosylase (AAG) by 3,N4-ethenocytosine containing DNA
Gondichatnahalli M. Lingaraju, C. Ainsley Davis, Jeremy W. Setser,
Leona D. Samson and Catherine L. Drennan
J. Biol. Chem.
doi:10.1074/jbc.M110.192435
Reactive oxygen and nitrogen species, generated by neutrophils and macrophages in chronically inflamed tissues, readily damage DNA, producing a variety of potentially genotoxic etheno base lesions; such inflammation-related DNA damage is now known to contribute to carcinogenesis.
While the human alkyladenine DNA glycosylase (AAG) can specifically bind DNA containing either 1,N6-ethenoadenine (εA) lesions or 3,N4-ethenocytosine (εC) lesions, it can only excise εA lesions. AAG binds very tightly to DNA containing εC lesions, forming an abortive protein-DNA complex; such binding not only shields εC from repair by other enzymes, but also inhibits AAG from acting on other DNA lesions.
To understand the structural basis for inhibition, we have characterized the binding of AAG to DNA containing εC lesions and have solved a crystal structure of AAG bound to a DNA duplex containing the εC lesion. This study provides the first structure of a DNA glycosylase in complex with an inhibitory base lesion that is induced endogenously and that is also induced upon exposure to environmental agents such as vinyl chloride. We identify the primary cause of inhibition as a failure to activate the nucleotide base as an efficient leaving group, and demonstrate that the higher binding affinity of AAG for εC versus εA is achieved through formation of an additional hydrogen bond between Asn169 in the active site pocket and the O2 of εC. This structure provides the basis for the design of AAG inhibitors currently being sought as an adjuvant for cancer chemotherapy. |
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Dow announces multiyear collaboration with MIT for innovative educational outreach
- Five-year, $2 million commitment will help develop and support careers of underrepresented minorities and women.
The Dow Chemical Company announced March 2, 2011, the establishment of the MIT-Dow Outreach Fund, which is designed to develop and support the science and engineering careers of underrepresented minorities and women. Read press release
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ASSISTANT PROFESSORS TO JOIN THE DEPARTMENT ON JULY 1 2011
Dr. Jeremiah Johnson, (top image) presently a Beckman Senior Research Fellow at CalTech, received his B.S. in chemistry and biomedical engineering in 2004 from Washington University and his Ph.D. from Columbia working with Prof. Nick Turro.
Dr. Brad Pentelute, (bottom image) presently an instructor at Harvard Medical School, received his B.S. in chemistry and B.A. in psychology in 2003 from University of Southern California and his Ph.D. from the University of Chicago working with Prof. Steve Kent.
Research in Dr. Johnson’s laboratory will seek to creatively integrate the tools of living polymerization, organic synthesis, microbiology, surface science, and photochemistry to solve problems at the interface of chemistry, biology, and materials engineering. Novel combinatorial synthetic schemes will be employed to generate libraries of nanoscopic and bulk materials for structure/function correlation in specific applications that include drug delivery, tissue engineering, biological imaging, sensing, catalysis, and energy conversion.
Dr. Pentelute’s goal is to develop an interdisciplinary laboratory of chemists and biologists that create the next generation chemical biology toolsets to understand virulence factors and D-proteins. He plans to work on a solution to the unmet problem of delivering stable, non-immunogenic, bioactive protein molecules to the cytosol of mammalian cells for therapeutic purposes. This goal will undoubtedly necessitate the production of new concepts and techniques in chemical biology.
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