Biomedical Sciences ETDs
Publication Date
Fall 5-13-2017
Abstract
The phosphodiester backbone of DNA is maintained by DNA ligases. In human cells, there are three genes that encode DNA ligase polypeptides with distinct but overlapping functions. A series of small molecule inhibitors of human DNA ligases were previously identified using a rational structure-based approach. Three of these inhibitors, L82, a DNA ligase I selective inhibitor, and L67, an inhibitor of DNA ligases I and III, and L189, an inhibitor of all three human DNA ligases, have related structures. Here I present and characterize L82-G17 a next-generation ligase I specific inhibitor. L82-G17 is a potent ligase I uncompetitive inhibitor that is shown to act both biochemically and in cell culture models. Furthermore, the binding site for L82 and L82-G17 has been identified via molecular modeling, and verified through mutagenesis.
Keywords
DNA Ligase, Molecular Modeling, Dissertation, Inhibitor, DNA Repair
Document Type
Thesis
Language
English
Degree Name
Biomedical Sciences
Level of Degree
Doctoral
Department Name
Biomedical Sciences Graduate Program
First Committee Member (Chair)
Alan Tomkinson
Second Committee Member
Mary Ann Osley
Third Committee Member
Tudor Oprea
Fourth Committee Member
Montaser Shaheen
Recommended Citation
Howes, Timothy RL. "Identification & Evaluation of DNA Ligase Inhibitors: Predicting the Binding of Small Molecules to the DNA Binding Domain by Molecular Modeling." (2017). https://digitalrepository.unm.edu/biom_etds/165
