ArticleProceedings of the National Academy of Sciences of the United States of America2014
Dimerization of HIV-1 protease occurs through two steps relating to the mechanism of protease dimerization inhibition by darunavir.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 77 citations in OpenAlex.
- Mechanisms of HIV-1 assembly, release and maturation.Nature reviews. Microbiology · 2026Review
- Conformational Dynamics of Viral Protease Precursors in Maturation, Inhibition, and Drug-Resistance Development.Viruses · 2026Review
- Engineering viral protease-operated nanobodies for programmable and orthogonal control of protein function.Nature communications · 2026Article
- Design, synthesis, evaluation and X-ray structural studies of potent HIV-1 protease inhibitors containing substituted oxaspirocyclic carbamates as the P2 ligands.European journal of medicinal chemistry · 2025Article
- An orally available P1'-5-fluorinated MPNAS nexus · 2025Article
- Interplay between protease and reverse transcriptase dimerization in a model HIV-1 polyprotein.Protein science : a publication of the Protein Society · 2024Article
- From Milliseconds to Minutes: Melittin Self-Assembly from Concerted Non-Equilibrium Pressure-Jump and Equilibrium Relaxation Nuclear Magnetic Resonance.The journal of physical chemistry letters · 2024Article
- Helical peptides with disordered regions for measles viruses provide new generalized insights into fusion inhibitors.iScience · 2024Article
- Conversion of raltegravir carrying a 1,3,4-oxadiazole ring to a hydrolysis product upon pH changes decreases its antiviral activity.PNAS nexus · 2024Article
- Evolution of drug resistance drives destabilization of flap region dynamics in HIV-1 protease.Biophysical reports · 2023Article
- Exploration of imatinib and nilotinib-derived templates as the P2-Ligand for HIV-1 protease inhibitors: Design, synthesis, protein X-ray structural studies, and biological evaluation.European journal of medicinal chemistry · 2023Article
- Comprehending the Structure, Dynamics, and Mechanism of Action of Drug-Resistant HIV Protease.ACS omega · 2023Review
- Evaluation of darunavir-derived HIV-1 protease inhibitors incorporating P2' amide-derivatives: Synthesis, biological evaluation and structural studies.Bioorganic & medicinal chemistry letters · 2023Article
- Identification of SARS-CoV-2 MNature communications · 2023Article
- Article
- Viral proteases as therapeutic targets.Molecular aspects of medicine · 2022Review
- Molecular Dynamics Study on Selected Bioactive Phytochemicals as Potential Inhibitors of HIV-1 Subtype C Protease.Metabolites · 2022Article
- Beyond darunavir: recent development of next generation HIV-1 protease inhibitors to combat drug resistance.Chemical communications (Cambridge, England) · 2022Review
- Cryo-EM structure of the HIV-1 Pol polyprotein provides insights into virion maturation.Science advances · 2022Article
- Serine hydroxymethyltransferase as a potential target of antibacterial agents acting synergistically with one-carbon metabolism-related inhibitors.Communications biology · 2022Article
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Authors and funding
10 authors at 5 institutions in 2 countries.
Funding
Abstract
Dimerization of HIV-1 protease (PR) subunits is an essential process for PR's acquisition of proteolytic activity, which plays a critical role in the maturation of HIV-1. Recombinant wild-type PR (PR(WT)) proved to dimerize, as examined with electrospray ionization mass spectrometry; however, two active site interface PR mutants (PR(T26A) and PR(R87K)) remained monomeric. On the other hand, two termini interface PR mutants (PR(1-C95A) and PR(97/99)) took both monomeric and dimeric forms. Differential scanning fluorimetry indicated that PR(1-C95A) and PR(97/99) dimers were substantially less stable than PR(WT) dimers. These data indicate that intermolecular interactions of two monomers occur first at the active site interface, generating unstable or transient dimers, and interactions at the termini interface subsequently occur, generating stable dimers. Darunavir (DRV), an HIV-1 protease inhibitor, inhibits not only proteolytic activity but also PR dimerization. DRV bound to protease monomers in a one-to-one molar ratio, inhibiting the first step of PR dimerization, whereas conventional protease inhibitors (such as saquinavir) that inhibit enzymatic activity but not dimerization failed to bind to monomers. DRV also bound to mutant PRs containing the transframe region-added PR (TFR-PR(D25N) and TFR-PR(D25N-7AA)), whereas saquinavir did not bind to TFR-PR(D25N) or TFR-PR(D25N-7AA). Notably, DRV failed to bind to mutant PR containing four amino acid substitutions (V32I, L33F, I54M, and I84V) that confer resistance to DRV on HIV-1. To our knowledge, the present report represents the first demonstration of the two-step PR dimerization dynamics and the mechanism of dimerization inhibition by DRV, which should help design further, more potent novel PIs.
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