Magnesium NMR of DNA Repair Proteins
EMSL Project ID
42592
Abstract
The chemistry central to the function of the DNA repair proteins apurinic/apyrimidic endonuclease 1 (APE1) and polymerase beta (pol beta) is the chemistry of water activated by a magnesium ion. These proteins are key constituents of the base excision repair (BER) pathway, a process that plays a critical role in preventing the cytotoxic and mutagenic effects of most spontaneous, alkylation and oxidative DNA damage. The proposed research represents a novel application of low temperature (10K) both static and MAS solid-state 25Mg NMR applied to DNA repair proteins and their model systems. The principal aim for the proposed research is to establish a relationship between 25Mg magnetic resonance parameters (quadrupole coupling constants, shielding tensors and their relative orientations) and the structure/function relationships for known Mg-DNA repair proteins and extrapolating those relationships to other Mg-dependent DNA repair proteins where the role of the metal is less defined. These Mg NMR experiments enable us to explore questions relative role Mg2+ plays in these two critical BER proteins. Additionally, these experiments lay the groundwork to understand the possible mode of action of small molecule inhibitors of DNA repair pathways. These experiments are performed in concert with ab initio electronic structure calculations. The combination of these two methods provides a firm basis for the 'chemical' understanding of the role these metals play in their respective proteins.
Project Details
Project type
Exploratory Research
Start Date
2011-02-14
End Date
2012-02-19
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members