ArticleJournal of molecular biology2005
Kinetic, stability, and structural changes in high-resolution crystal structures of HIV-1 protease with drug-resistant mutations L24I, I50V, and G73S.
Article in Journal of molecular biology, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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36 citing papers in PubMed, 84 citations in OpenAlex.
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- Premature Activation of the HIV-1 Protease Is Influenced by Polymorphisms in the Hinge Region.Viruses · 2024Article
- Chemical features and machine learning assisted predictions of protein-ligand short hydrogen bonds.Scientific reports · 2023Article
- Systematic Analyses of the Resistance Potential of Drugs Targeting SARS-CoV-2 Main Protease.ACS infectious diseases · 2023Article
- Chemical Features and Machine Learning Assisted Predictions of Protein-Ligand Short Hydrogen Bonds.Research square · 2023Article
- Highly drug-resistant HIV-1 protease reveals decreased intra-subunit interactions due to clusters of mutations.The FEBS journal · 2020Article
- Impacts of drug resistance mutations on the structural asymmetry of the HIV-2 protease.BMC molecular and cell biology · 2020Article
- Non-active site mutants of HIV-1 protease influence resistance and sensitisation towards protease inhibitors.Retrovirology · 2020Article
- Dimer Interface Organization is a Main Determinant of Intermonomeric Interactions and Correlates with Evolutionary Relationships of Retroviral and Retroviral-Like Ddi1 and Ddi2 Proteases.International journal of molecular sciences · 2020Article
- Characterizing early drug resistance-related events using geometric ensembles from HIV protease dynamics.Scientific reports · 2018Article
- Unique Flap Conformation in an HIV-1 Protease with High-Level Darunavir Resistance.Frontiers in microbiology · 2016Article
- Structures of darunavir-resistant HIV-1 protease mutant reveal atypical binding of darunavir to wide open flaps.ACS chemical biology · 2014Article
- Novel P2 tris-tetrahydrofuran group in antiviral compound 1 (GRL-0519) fills the S2 binding pocket of selected mutants of HIV-1 protease.Journal of medicinal chemistry · 2013Article
- Conserved hydrogen bonds and water molecules in MDR HIV-1 protease substrate complexes.Biochemical and biophysical research communications · 2013Article
- Inhibition of XMRV and HIV-1 proteases by pepstatin A and acetyl-pepstatin.The FEBS journal · 2012Article
- Transition states of native and drug-resistant HIV-1 protease are the same.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
- Rational approaches to improving selectivity in drug design.Journal of medicinal chemistry · 2012Review
- Enhancing protein backbone binding--a fruitful concept for combating drug-resistant HIV.Angewandte Chemie (International ed. in English) · 2012Review
- Quantitative predictions of binding free energy changes in drug-resistant influenza neuraminidase.PLoS computational biology · 2012Article
- Accessory mutations maintain stability in drug-resistant HIV-1 protease.Journal of molecular biology · 2011Article
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
The crystal structures, dimer stabilities, and kinetics have been analyzed for wild-type human immunodeficiency virus type 1 (HIV-1) protease (PR) and resistant mutants PR(L24I), PR(I50V), and PR(G73S) to gain insight into the molecular basis of drug resistance. The mutations lie in different structural regions. Mutation I50V alters a residue in the flexible flap that interacts with the inhibitor, L24I alters a residue adjacent to the catalytic Asp25, and G73S lies at the protein surface far from the inhibitor-binding site. PR(L24I) and PR(I50V), showed a 4% and 18% lower k(cat)/K(m), respectively, relative to PR. The relative k(cat)/K(m) of PR(G73S) varied from 14% to 400% when assayed using different substrates. Inhibition constants (K(i)) of the antiviral drug indinavir for the reaction catalyzed by the mutant enzymes were about threefold and 50-fold higher for PR(L24I) and PR(I50V), respectively, relative to PR and PR(G73S). The dimer dissociation constant (K(d)) was estimated to be approximately 20 nM for both PR(L24I) and PR(I50V), and below 5 nM for PR(G73S) and PR. Crystal structures of the mutants PR(L24I), PR(I50V) and PR(G73S) were determined in complexes with indinavir, or the p2/NC substrate analog at resolutions of 1.10-1.50 Angstrom. Each mutant revealed distinct structural changes relative to PR. The mutated residues in PR(L24I) and PR(I50V) had reduced intersubunit contacts, consistent with the increased K(d) for dimer dissociation. Relative to PR, PR(I50V) had fewer interactions of Val50 with inhibitors, in agreement with the dramatically increased K(i). The distal mutation G73S introduced new hydrogen bond interactions that can transmit changes to the substrate-binding site and alter catalytic activity. Therefore, the structural alterations observed for drug-resistant mutations were in agreement with kinetic and stability changes.
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