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Human Neil2 DNA glycosylase - crystal and inhibitor screening, and mutational analysis

Zhang, Simeng
Master thesis
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thesis-final-version.pdf (7.632Mb)
Year
2016
Permanent link
http://urn.nb.no/URN:NBN:no-55796

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  • Molekylærbiologi [213]
Abstract
Base excision repair (BER) is the major pathway for repairing oxidative DNA damages. This pathway is initiated by different DNA glycosylases. DNA glycosylases can recognise and remove DNA base lesions, and are also potential drug targets in cancer therapy. Nei-like 2 (Neil2) protein, a glycosylase in the Fpg/Nei superfamily, is a trifunctional enzyme, exhibiting glycosylase activity and AP lyase activity at both the 3’ and 5’ termini of AP sites. However, there is no available crystal structure for human Neil2 at present. In this thesis, different crystallisation conditions were used in trying to obtain crystals of full-length human Neil2, a truncated human Neil2 as well as Neil2-DNA complexes. In addition, different full-length human Neil2 mutants were used to study the potential active sites that are responsible for Neil2 AP lyase activity. We show that residues Pro2, Lys50 and Lys51 are all essential for Neil2 AP lyase activity. At last, 44 compounds were selected by docking to the known structure of human Neil1, which is a homolog protein of Neil2. The affinity between those compounds and the wild type full-length human Neil2 was studied experimentally. Two potential inhibitors of Neil2 were found by the AP lyase activity assay. The Kd values for the two inhibitors, ligands 20 and 34, are 13±2.5μM and 92±40μM, respectively. The IC50 value is 80μM for both inhibitors.
 
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