Mimicking damaged DNA with a small molecule inhibitor of human UNG2

Daniel J. Krosky, Mario Antonio Bianchet, Lauren Seiple, Suhman Chung, Mario L Amzel, James Stivers

Research output: Contribution to journalArticle

Abstract

Human nuclear uracil DNA glycosylase (UNG2) is a cellular DNA repair enzyme that is essential for a number of diverse biological phenomena ranging from antibody diversification to B-cell lymphomas and type-1 human immunodeficiency virus infectivity. During each of these processes, UNG2 recognizes uracilated DNA and excises the uracil base by flipping it into the enzyme active site. We have taken advantage of the extrahelical uracil recognition mechanism to build large small-molecule libraries in which uracil is tethered via flexible alkane linkers to a collection of secondary binding elements. This high-throughput synthesis and screening approach produced two novel uracil-tethered inhibitors of UNG2, the best of which was crystallized with the enzyme. Remarkably, this inhibitor mimics the crucial hydrogen bonding and electrostatic interactions previously observed in UNG2 complexes with damaged uracilated DNA. Thus, the environment of the binding site selects for library ligands that share these DNA features. This is a general approach to rapid discovery of inhibitors of enzymes that recognize extrahelical damaged bases.

Original languageEnglish (US)
Pages (from-to)5872-5879
Number of pages8
JournalNucleic Acids Research
Volume34
Issue number20
DOIs
StatePublished - Nov 2006

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Uracil
DNA
Uracil-DNA Glycosidase
Small Molecule Libraries
DNA Repair Enzymes
Biological Phenomena
Alkanes
B-Cell Lymphoma
Enzyme Inhibitors
Enzymes
Hydrogen Bonding
Static Electricity
Libraries
HIV-1
Catalytic Domain
Binding Sites
Ligands
Antibodies

ASJC Scopus subject areas

  • Genetics

Cite this

Mimicking damaged DNA with a small molecule inhibitor of human UNG2. / Krosky, Daniel J.; Bianchet, Mario Antonio; Seiple, Lauren; Chung, Suhman; Amzel, Mario L; Stivers, James.

In: Nucleic Acids Research, Vol. 34, No. 20, 11.2006, p. 5872-5879.

Research output: Contribution to journalArticle

Krosky, Daniel J. ; Bianchet, Mario Antonio ; Seiple, Lauren ; Chung, Suhman ; Amzel, Mario L ; Stivers, James. / Mimicking damaged DNA with a small molecule inhibitor of human UNG2. In: Nucleic Acids Research. 2006 ; Vol. 34, No. 20. pp. 5872-5879.
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