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Subtype polymorphisms among HIV-1 protease variants confer altered flap conformations and flexibility.

Abstract
Human immunodeficiency virus type 1 (HIV-1) protease plays a fundamental role in the maturation and life cycle of the retrovirus HIV-1, as it functions in regulating post-translational processing of the viral polyproteins gag and gag-pol; thus, it is a key target of AIDS antiviral therapy. Accessibility of substrate to the active site is mediated by two flaps, which must undergo a large conformational change from an open to a closed conformation during substrate binding and catalysis. The electron paramagnetic resonance (EPR) method of site-directed spin labeling (SDSL) with double electron-electron resonance (DEER) spectroscopy was utilized to monitor the conformations of the flaps in apo HIV-1 protease (HIV-1PR), subtypes B, C, and F, CRF01_A/E, and patient isolates V6 and MDR 769. The distance distribution profiles obtained from analysis of the dipolar modulated echo curves were reconstructed to yield a set of Gaussian-shaped populations, which provide an analysis of the flap conformations sampled. The relative percentages of each conformer population described as "tucked/curled", "closed", "semi-open", and "wide-open" were determined and compared for various constructs. The results and analyses show that sequence variations among subtypes, CRFs, and patient isolates of apo HIV-1PR alter the average flap conformation in a way that can be understood as inducing shifts in the relative populations, or conformational sampling, of the previously described four conformations for HIV-1PR.
AuthorsJamie L Kear, Mandy E Blackburn, Angelo M Veloro, Ben M Dunn, Gail E Fanucci
JournalJournal of the American Chemical Society (J Am Chem Soc) Vol. 131 Issue 41 Pg. 14650-1 (Oct 21 2009) ISSN: 1520-5126 [Electronic] United States
PMID19788299 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • HIV Protease Inhibitors
  • Isoenzymes
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1
Topics
  • Catalytic Domain
  • HIV Protease (chemistry, genetics, metabolism)
  • HIV Protease Inhibitors (pharmacology)
  • Isoenzymes (antagonists & inhibitors, chemistry, genetics, metabolism)
  • Models, Molecular
  • Polymorphism, Genetic

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