We have continued our efforts to modify and improve NMR methodologies for the assignment of resonances and the analysis of molecular structure and dynamics, and to apply these approaches to problems related to environmental health. One of the central problems inherent in the analysis of complex molecules using NMR is the complexity of the spectra resulting from the large number of overlapping resonances. Several new strategies for obtaining edited 2-dimensional NMR spectra which overcame the limitations resulting from the large number of resonances have been evaluated over the past year. In collaboration with Dr. Morrow Thompson of DTRT, some of these methods have been applied to the analysis of bile acid adducts obtained subsequent to the treatment of rats with a-naphthyl isothiocyanate (ANIT) which causes bile duct necrosis. Two new structural NMR efforts, both related to AIDS research, were also initiated during the past year. The first is a collaborative effort with Dr. Robert Handschumacher on the enzyme cyclophilin, the apparent target of the immunosuppressive drug cyclosporin A. It has recently been demonstrated that cyclophilin catalyzes the cis/trans isomerization of peptidyl-proline bonds; however, the physiologically important targets of this enzyme have yet to be identified. It was proposed that the biologically active peptide bradykinin might be a substrate for this enzyme, and fluorinated analogs of bradykinin which can be monitored with fluorine-19 NMR were prepared by Dr. John Stewart of the University of Colorado. It has been determined that the cis/trans isomerization rate constants of both bradykinin and its [Gly6]-bradykinin analog are significantly increased in the presence of the enzyme. A second structural study initiated during the past year is aimed at determining the conformation of inhibitors of the enzyme purine nucleoside phosphorylase (PNPase), which is important in the catabolism of nucleoside drugs used to treat a variety of illnesses, as well as in the synthesis of the these drugs.
| 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 |
| 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 |
| 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 |
| 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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