NMR Structural Studies of HIV-1 Protease/Inhibitor Complexes

Torchia, D A.

Abstract

The HIV protease is a leading candidate for targeted antiviral drug design because inhibition of this enzyme results in production of non-infectious virions. We are investigating the molecular structure and dynamics of the HIV-1 protease complexed with highly potent and specific inhibitors of the viral enzyme. In addition, we are measuring the protonation states and pKa's of its catalytic aspartyl residues, and its interactions with solvent molecules. Similar studies of the free protease are also underway. This work is the first comprehensive biophysical characterization of the HIV-1 protease and protease/inhibitor complex in solution.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Dental & Craniofacial Research (NIDCR)
• Type: Intramural Research (Z01)
• Project #: 1Z01DE000507-07
• Application #: 2572341
• Study Section: Special Emphasis Panel (ODIR)
• Support Year: 7
• Fiscal Year: 1996

Institution

• Name: National Institute of Dental & Craniofacial Research
• Country: United States

Publications

Ishima, Rieko; Torchia, Dennis A (2006) Accuracy of optimized chemical-exchange parameters derived by fitting CPMG R2 dispersion profiles when R2(0a) not = R2(0b). J Biomol NMR 34:209-19

Ishima, Rieko; Torchia, Dennis A (2005) Error estimation and global fitting in transverse-relaxation dispersion experiments to determine chemical-exchange parameters. J Biomol NMR 32:41-54

Ishima, Rieko; Baber, James; Louis, John M et al. (2004) Carbonyl carbon transverse relaxation dispersion measurements and ms-micros timescale motion in a protein hydrogen bond network. J Biomol NMR 29:187-98

Jacob, Jaison; Louis, John M; Richter, B W M et al. (2004) The C-terminal domain of viral IAP associated factor (cVIAF) is a structural homologue of phosducin: resonance assignments and secondary structure of the C-terminal domain of VIAF. J Biomol NMR 28:197-8

Ishima, Rieko; Torchia, Dennis A (2003) Extending the range of amide proton relaxation dispersion experiments in proteins using a constant-time relaxation-compensated CPMG approach. J Biomol NMR 25:243-8

Ishima, Rieko; Torchia, Dennis A; Lynch, Shannon M et al. (2003) Solution structure of the mature HIV-1 protease monomer: insight into the tertiary fold and stability of a precursor. J Biol Chem 278:43311-9

Louis, John M; Ishima, Rieko; Nesheiwat, Issa et al. (2003) Revisiting monomeric HIV-1 protease. Characterization and redesign for improved properties. J Biol Chem 278:6085-92

Katoh, Etsuko; Louis, John M; Yamazaki, Toshimasa et al. (2003) A solution NMR study of the binding kinetics and the internal dynamics of an HIV-1 protease-substrate complex. Protein Sci 12:1376-85

Freedberg, Daron I; Ishima, Rieko; Jacob, Jaison et al. (2002) Rapid structural fluctuations of the free HIV protease flaps in solution: relationship to crystal structures and comparison with predictions of dynamics calculations. Protein Sci 11:221-32

Korzhnev, Dmitry M; Skrynnikov, Nikolai R; Millet, Oscar et al. (2002) An NMR experiment for the accurate measurement of heteronuclear spin-lock relaxation rates. J Am Chem Soc 124:10743-53