ArticleProteins2009
Interactions of different inhibitors with active-site aspartyl residues of HIV-1 protease and possible relevance to pepsin.
Article in Proteins, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 26 citations in OpenAlex.
- Gatherings in Esophagology: Innovations and Future Directions in the Diagnosis and Management of Reflux Disease.Annals of the New York Academy of Sciences · 2026Article
- Amprenavir Mitigates Pepsin-Induced Transcriptomic Changes in Normal and Precancerous Esophageal Cells.International journal of molecular sciences · 2025Article
- Exploring the effect of ritonavir and TMC-310911 on SARS-CoV-2 and SARS-CoV main proteases: potential from a molecular perspective.Future science OA · 2020Article
- Sensing HIV Protease and Its Inhibitor Using "Helical Epitope"-Imprinted Polymers.Sensors (Basel, Switzerland) · 2020Article
- Class A G Protein-Coupled Receptor Antagonist Famotidine as a Therapeutic Alternative Against SARS-CoV2: An In Silico Analysis.Biomolecules · 2020Article
- Evolution under Drug Pressure Remodels the Folding Free-Energy Landscape of Mature HIV-1 Protease.Journal of molecular biology · 2016Article
- 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
- Dimerization of HIV-1 protease occurs through two steps relating to the mechanism of protease dimerization inhibition by darunavir.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- The role of select subtype polymorphisms on HIV-1 protease conformational sampling and dynamics.The Journal of biological chemistry · 2014Article
- HIV-1 protease with 20 mutations exhibits extreme resistance to clinical inhibitors through coordinated structural rearrangements.Biochemistry · 2012Article
- Dynamics of thermodynamically stable, kinetically trapped, and inhibitor-bound states of pepsin.Biophysical journal · 2011Article
- Inhibition of autoprocessing of natural variants and multidrug resistant mutant precursors of HIV-1 protease by clinical inhibitors.Proceedings of the National Academy of Sciences of the United States of America · 2011Article
- The L76V drug resistance mutation decreases the dimer stability and rate of autoprocessing of HIV-1 protease by reducing internal hydrophobic contacts.Biochemistry · 2011Article
- 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
- Revealing the dimer dissociation and existence of a folded monomer of the mature HIV-2 protease.Protein science : a publication of the Protein Society · 2009Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The importance of the active site region aspartyl residues 25 and 29 of the mature HIV-1 protease (PR) for the binding of five clinical and three experimental protease inhibitors [symmetric cyclic urea inhibitor DMP323, nonhydrolyzable substrate analog (RPB) and the generic aspartic protease inhibitor acetyl-pepstatin (Ac-PEP)] was assessed by differential scanning calorimetry. DeltaT(m) values, defined as the difference in T(m) for a given protein in the presence and absence of inhibitor, for PR with DRV, ATV, SQV, RTV, APV, DMP323, RPB, and Ac-PEP are 22.4, 20.8, 19.3, 15.6, 14.3, 14.7, 8.7, and 6.5 degrees C, respectively. Binding of APV and Ac-PEP is most sensitive to the D25N mutation, as shown by DeltaT(m) ratios [DeltaT(m)(PR)/DeltaT(m)(PR(D25N))] of 35.8 and 16.3, respectively, whereas binding of DMP323 and RPB (DeltaT(m) ratios of 1-2) is least affected. Binding of the substrate-like inhibitors RPB and Ac-PEP is nearly abolished (DeltaT(m)(PR)/DeltaT(m)(PR(D29N)) > or = 44) by the D29N mutation, whereas this mutation only moderately affects binding of the smaller inhibitors (DeltaT(m) ratios of 1.4-2.2). Of the nine FDA-approved clinical HIV-1 protease inhibitors screened, APV, RTV, and DRV competitively inhibit porcine pepsin with K(i) values of 0.3, 0.6, and 2.14 microM, respectively. DSC results were consistent with this relatively weak binding of APV (DeltaT(m) 2.7 degrees C) compared with the tight binding of Ac-PEP (DeltaT(m) > or = 17 degrees C). Comparison of superimposed structures of the PR/APV complex with those of PR/Ac-PEP and pepsin/pepstatin A complexes suggests a role for Asp215, Asp32, and Ser219 in pepsin, equivalent to Asp25, Asp25', and Asp29 in PR in the binding and stabilization of the pepsin/APV complex.
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