The aims of this project are: (1) to develop and modify NMR methodologies for the assignment of resonances and the analysis of the structure and dynamics of molecules in solution, and (2) to apply these methods to problems of concern in relation to environmental health. During the past year, the primary emphasis of this project has been in two areas: (1) development of the transferred NOE (TRNOE) technique and its application to the determination of the conformation of the nucleoside drug tubercidin in the complex with E. coli purine nucleoside phosphorylase (PNPase), and (2) analysis of the interaction of benzeneboronic acid (BBA) derivatives with small molecules and with the enzyme subtilisin. An important objective of both problems was a characterization of the kinetic behavior. Specifically, we have previously determined that the TRNOE parameters for inhibitors which are exchanging with macromolecular binding sites can be strongly dependent on the exchange rates. We have recently evaluated the use of two strategies for determining ligand exchange rates: (1) Measurement of T2 using the CPMG technique as a function of pulse rate, and (2) measurement of the T1o values for the ligand as a function of the strength of the spin-lock field. We are currently carrying out detailed theoretical and experimental analyses of these experiments in the PNPase - tubercidin system. In the second area, studies with BBA derivatives have determined apparent dissociation constants with various biologically significant ligands under physiological conditions, as well as binding kinetics. The binding kinetics of 4-fluoroBBA with the serine protease subtilisin were compared with results obtained on various model ligands in order to characterize the interaction with the enzyme.
| Wallace, Bret D; Berman, Zachary; Mueller, Geoffrey A et al. (2017) APE2 Zf-GRF facilitates 3'-5' resection of DNA damage following oxidative stress. Proc Natl Acad Sci U S A 114:304-309 |
| Gabel, Scott A; Smith, Cassandra E; Cuneo, Matthew J et al. (2014) Characterization of the redox transition of the XRCC1 N-terminal domain. Structure 22:1754-1763 |
| Gabel, Scott A; DeRose, Eugene F; London, Robert E (2013) XRCC1 interaction with the REV1 C-terminal domain suggests a role in post replication repair. DNA Repair (Amst) 12:1105-13 |
| Loeffler, Paul A; Cuneo, Matthew J; Mueller, Geoffrey A et al. (2011) Structural studies of the PARP-1 BRCT domain. BMC Struct Biol 11:37 |
| Butterfoss, Glenn L; DeRose, Eugene F; Gabel, Scott A et al. (2010) Conformational dependence of 13C shielding and coupling constants for methionine methyl groups. J Biomol NMR 48:31-47 |
| London, Robert E; Wingad, Brett D; Mueller, Geoffrey A (2008) Dependence of amino acid side chain 13C shifts on dihedral angle: application to conformational analysis. J Am Chem Soc 130:11097-105 |
| DeRose, Eugene F; Clarkson, Michael W; Gilmore, Steven A et al. (2007) Solution structure of polymerase mu's BRCT Domain reveals an element essential for its role in nonhomologous end joining. Biochemistry 46:12100-10 |
| DellaVecchia, Matthew J; Merritt, W Keither; Peng, Ye et al. (2007) NMR analysis of [methyl-13C]methionine UvrB from Bacillus caldotenax reveals UvrB-domain 4 heterodimer formation in solution. J Mol Biol 373:282-95 |
| Krahn, Joseph M; Jackson, Michael R; DeRose, Eugene F et al. (2007) Crystal structure of a type II dihydrofolate reductase catalytic ternary complex. Biochemistry 46:14878-88 |
| London, Robert E; Gabel, Scott A (2006) Photoactivated h/d exchange in tyrosine: involvement of a radical anion intermediate. J Am Chem Soc 128:2268-75 |
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