ArticlePloS one2016
Structural Studies of a Rationally Selected Multi-Drug Resistant HIV-1 Protease Reveal Synergistic Effect of Distal Mutations on Flap Dynamics.
Article in PloS one, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 51 citations in OpenAlex.
- 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
- Predicting the Impact of Drug Resistance Mutations on Inhibitor Potency with Molecular Dynamics and Machine Learning.The journal of physical chemistry. B · 2025Article
- Benchmarking Machine Learning Models for HIV-1 Protease Inhibitor Resistance Prediction: Impact of Data Set Construction and Feature Representation.Journal of chemical information and modeling · 2025Article
- Enzyme-substrate co-display on yeast empowers engineering of tobacco etch virus protease activity.Protein engineering, design & selection : PEDS · 2025Article
- Design, Synthesis, and Biological Evaluation of Darunavir Analogs as HIV-1 Protease Inhibitors.ACS bio & med chem Au · 2024Article
- Premature Activation of the HIV-1 Protease Is Influenced by Polymorphisms in the Hinge Region.Viruses · 2024Article
- Article
- HIV-1 protease with 10 lopinavir and darunavir resistance mutations exhibits altered inhibition, structural rearrangements and extreme dynamics.Journal of molecular graphics & modelling · 2022Article
- Prune homolog 2 with BCH domain (PRUNE2) gene expression is associated with feed efficiency-related traits in Nelore steers.Mammalian genome : official journal of the International Mammalian Genome Society · 2022Article
- Age-associated changes in gene expression in the anterior pituitary glands of female Japanese black cattle.Mammalian genome : official journal of the International Mammalian Genome Society · 2022Article
- Assessment of a Computational Approach to Predict Drug Resistance Mutations for HIV, HBV and SARS-CoV-2.Molecules (Basel, Switzerland) · 2022Article
- Multiple Molecular Dynamics Simulations and Energy Analysis Unravel the Dynamic Properties and Binding Mechanism of Mutants HIV-1 Protease with DRV and CA-p2.Microbiology spectrum · 2022Article
- Prediction and molecular field view of drug resistance in HIV-1 protease mutants.Scientific reports · 2022Article
- The structural, dynamic, and thermodynamic basis of darunavir resistance of a heavily mutated HIV-1 protease using molecular dynamics simulation.Frontiers in molecular biosciences · 2022Article
- Revertant mutation V48G alters conformational dynamics of highly drug resistant HIV protease PRS17.Journal of molecular graphics & modelling · 2021Article
- Novel HIV PR inhibitors with C4-substituted bis-THF and bis-fluoro-benzyl target the two active site mutations of highly drug resistant mutant PRBiochemical and biophysical research communications · 2021Article
- Review
- Structural Impacts of Drug-Resistance Mutations Appearing in HIV-2 Protease.Molecules (Basel, Switzerland) · 2021Article
- Darunavir-Resistant HIV-1 Protease Constructs Uphold a Conformational Selection Hypothesis for Drug Resistance.Viruses · 2020Article
- Highly drug-resistant HIV-1 protease reveals decreased intra-subunit interactions due to clusters of mutations.The FEBS journal · 2020Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
We report structural analysis of HIV protease variant PRS17 which was rationally selected by machine learning to represent wide classes of highly drug-resistant variants. Crystal structures were solved of PRS17 in the inhibitor-free form and in complex with antiviral inhibitor, darunavir. Despite its 17 mutations, PRS17 has only one mutation (V82S) in the inhibitor/substrate binding cavity, yet exhibits high resistance to all clinical inhibitors. PRS17 has none of the major mutations (I47V, I50V, I54ML, L76V and I84V) associated with darunavir resistance, but has 10,000-fold weaker binding affinity relative to the wild type PR. Comparable binding affinity of 8000-fold weaker than PR is seen for drug resistant mutant PR20, which bears 3 mutations associated with major resistance to darunavir (I47V, I54L and I84V). Inhibitor-free PRS17 shows an open flap conformation with a curled tip correlating with G48V flap mutation. NMR studies on inactive PRS17 D25N unambiguously confirm that the flaps adopt mainly an open conformation in solution very similar to that in the inhibitor-free crystal structure. In PRS17, the hinge loop cluster of mutations, E35D, M36I and S37D, contributes to the altered flap dynamics by a mechanism similar to that of PR20. An additional K20R mutation anchors an altered conformation of the hinge loop. Flap mutations M46L and G48V in PRS17/DRV complex alter the Phe53 conformation by steric hindrance between the side chains. Unlike the L10F mutation in PR20, L10I in PRS17 does not break the inter-subunit ion pair or diminish the dimer stability, consistent with a very low dimer dissociation constant comparable to that of wild type PR. Distal mutations A71V, L90M and I93L propagate alterations to the catalytic site of PRS17. PRS17 exhibits a molecular mechanism whereby mutations act synergistically to alter the flap dynamics resulting in significantly weaker binding yet maintaining active site contacts with darunavir.
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