HIV protease is an important chemotherapeutic target for the treatment of AIDS; the most successful treatments developed to date involve combinations of protease inhibitors with nucleoside analogs which inhibit the reverse transcriptase. However, the high mutation rate of the virus makes it possible to select against most of the protease inhibitors which thus far have been developed. Recent work on this project has included several goals: 1. Development of HIV protease mutants with greater stability, particularly to allow NMR studies of the uncomplexed enzyme; 2. Evaluation of a new inhibition strategy based on the use of inhibitors with multiple binding modes; 3. Development of a new NMR approach for inhibitor design. The latter method, called the inter-ligand Overhauser effect, allows the investigation of structural relationships between weakly bound ligands so that they can be combined to yield a single, more potent inhibitor. - HIV protease; proline; NMR; nuclear Overhauser effect; inhibitor binding

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Intramural Research (Z01)
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Zheng, Xunhai; Mueller, Geoffrey A; Kim, Kyungmin et al. (2017) Identification of drivers for the metamorphic transition of HIV-1 reverse transcriptase. Biochem J 474:3321-3338
London, Robert E (2016) Structural Maturation of HIV-1 Reverse Transcriptase-A Metamorphic Solution to Genomic Instability. Viruses 8:
Zheng, Xunhai; Pedersen, Lars C; Gabel, Scott A et al. (2016) Unfolding the HIV-1 reverse transcriptase RNase H domain--how to lose a molecular tug-of-war. Nucleic Acids Res 44:1776-88
Zheng, Xunhai; Perera, Lalith; Mueller, Geoffrey A et al. (2015) Asymmetric conformational maturation of HIV-1 reverse transcriptase. Elife 4:
Kirby, Thomas W; Derose, Eugene F; Beard, William A et al. (2014) Substrate rescue of DNA polymerase ? containing a catastrophic L22P mutation. Biochemistry 53:2413-22
Zheng, Xunhai; Pedersen, Lars C; Gabel, Scott A et al. (2014) Selective unfolding of one Ribonuclease H domain of HIV reverse transcriptase is linked to homodimer formation. Nucleic Acids Res 42:5361-77
Horton, Julie K; Stefanick, Donna F; Gassman, Natalie R et al. (2013) Preventing oxidation of cellular XRCC1 affects PARP-mediated DNA damage responses. DNA Repair (Amst) 12:774-85
Zheng, Xunhai; Mueller, Geoffrey A; DeRose, Eugene F et al. (2013) Protein-mediated antagonism between HIV reverse transcriptase ligands nevirapine and MgATP. Biophys J 104:2695-705
Zheng, Xunhai; Mueller, Geoffrey A; DeRose, Eugene F et al. (2012) Metal and ligand binding to the HIV-RNase H active site are remotely monitored by Ile556. Nucleic Acids Res 40:10543-53
Zheng, Xunhai; Mueller, Geoffrey A; Cuneo, Matthew J et al. (2010) Homodimerization of the p51 subunit of HIV-1 reverse transcriptase. Biochemistry 49:2821-33

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