ArticleProtein science : a publication of the Protein Society2009
Revealing the dimer dissociation and existence of a folded monomer of the mature HIV-2 protease.
Article in Protein science : a publication of the Protein Society, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed.
- Conformational asymmetry of human immunodeficiency virus-1 protease flaps increases along the darunavir drug resistance pathway.Protein science : a publication of the Protein Society · 2026Article
- Interplay between protease and reverse transcriptase dimerization in a model HIV-1 polyprotein.Protein science : a publication of the Protein Society · 2024Article
- HIV-2 Immature Particle Morphology Provides Insights into Gag Lattice Stability and Virus Maturation.Journal of molecular biology · 2023Article
- Antiretroviral Treatment of HIV-2 Infection: Available Drugs, Resistance Pathways, and Promising New Compounds.International journal of molecular sciences · 2023Review
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- Structural studies of antiviral inhibitor with HIV-1 protease bearing drug resistant substitutions of V32I, I47V and V82I.Biochemical and biophysical research communications · 2019Article
- Highly Drug-Resistant HIV-1 Protease Mutant PRS17 Shows Enhanced Binding to Substrate Analogues.ACS omega · 2019Article
- Inhibition of HIV Maturation via Selective Unfolding and Cross-Linking of Gag Polyprotein by a Mercaptobenzamide Acetylator.Journal of the American Chemical Society · 2019Article
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- Mutations Proximal to Sites of Autoproteolysis and the α-Helix That Co-evolve under Drug Pressure Modulate the Autoprocessing and Vitality of HIV-1 Protease.Biochemistry · 2015Article
- A Direct Interaction with RNA Dramatically Enhances the Catalytic Activity of the HIV-1 Protease In Vitro.Journal of molecular biology · 2015Article
- Article
- Structures of darunavir-resistant HIV-1 protease mutant reveal atypical binding of darunavir to wide open flaps.ACS chemical biology · 2014Article
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- Enhanced stability of monomer fold correlates with extreme drug resistance of HIV-1 protease.Biochemistry · 2013Article
- Mechanism of dissociative inhibition of HIV protease and its autoprocessing from a precursor.Journal of molecular biology · 2012Article
- Critical differences in HIV-1 and HIV-2 protease specificity for clinical inhibitors.Protein science : a publication of the Protein Society · 2012Article
- Autocatalytic maturation, physical/chemical properties, and crystal structure of group N HIV-1 protease: relevance to drug resistance.Protein science : a publication of the Protein Society · 2010Article
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4 authors.
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Abstract
Purification and in vitro protein-folding schemes were developed to produce monodisperse samples of the mature wild-type HIV-2 protease (PR2), enabling a comprehensive set of biochemical and biophysical studies to assess the dissociation of the dimeric protease. An E37K substitution in PR2 significantly retards autoproteolytic cleavage during expression. Furthermore, it permits convenient measurement of the dimer dissociation of PR2(E37K) (elevated K(d) approximately 20 nM) by enzyme kinetics. Differential scanning calorimetry reveals a T(m) of 60.5 for PR2 as compared with 65.7 degrees C for HIV-1 protease (PR1). Consistent with weaker binding of the clinical inhibitor darunavir (DRV) to PR2, the T(m) of PR2 increases by 14.8 degrees C in the presence of DRV as compared with 22.4 degrees C for PR1. Dimer interface mutations, such as a T26A substitution in the active site (PR2(T26A)) or a deletion of the C-terminal residues 96-99 (PR2(1-95)), drastically increase the K(d) (>10(5)-fold). PR2(T26A) and PR2(1-95) consist predominantly of folded monomers, as determined by nuclear magnetic resonance (NMR) and size-exclusion chromatography coupled with multiangle light scattering and refractive index measurements (SMR), whereas wild-type PR2 and its active-site mutant PR2(D25N) are folded dimers. Addition of twofold excess active-site inhibitor promotes dimerization of PR2(T26A) but not of PR2(1-95), indicating that subunit interactions involving the C-terminal residues are crucial for dimer formation. Use of SMR and NMR with PR2 facilitates probing for potential inhibitors that restrict protein folding and/or dimerization and, thus, may provide insights for the future design of inhibitors to circumvent drug resistance.
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