ArticleProceedings of the National Academy of Sciences of the United States of America2014
Structural basis and distal effects of Gag substrate coevolution in drug resistance to HIV-1 protease.
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 33 papers, 1 of them a synthesis that pooled it.
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Who cites it
33 citing papers in PubMed, 1 synthesis or guideline pooled it, 49 citations in OpenAlex.
- HIV Genome-Wide Protein Associations: a Review of 30 Years of Research.Microbiology and molecular biology reviews : MMBR · 2016Pooled it
- Different mechanisms for human rhinovirus survival in the presence of deleterious amino acid substitutions at virion protein-protein or RNA-protein interfaces.Journal of virology · 2026Article
- Mutational scan of self-cleavage by HIV-1 protease provides new views of a conformationally dynamic mechanism.Journal of virology · 2026Article
- Fluorinated HIV-1 protease inhibitors containing chiral hydroxyethylbenzene and indanol as P2' ligands with potent activity against drug-resistant variants.European journal of medicinal chemistry · 2026Article
- Mutational scan of self-cleavage by HIV-1 protease provides new views of a conformationally dynamic mechanism.bioRxiv : the preprint server for biology · 2025Article
- Premature Activation of the HIV-1 Protease Is Influenced by Polymorphisms in the Hinge Region.Viruses · 2024Article
- Article
- HIV-1 envelope facilitates the development of protease inhibitor resistance through acquiring mutations associated with viral entry and immune escape.Frontiers in microbiology · 2024Article
- HIV-1 protease inhibitors with a P1 phosphonate modification maintain potency against drug-resistant variants by increased interactions with flap residues.European journal of medicinal chemistry · 2023Article
- Article
- OPUS-Mut: Studying the Effect of Protein Mutation through Side-Chain Modeling.Journal of chemical theory and computation · 2023Article
- Sequence dependencies and biophysical features both govern cleavage of diverse cut-sites by HIV protease.Protein science : a publication of the Protein Society · 2022Article
- Elasticity-Associated Functionality and Inhibition of the HIV Protease.Advances in experimental medicine and biology · 2022Article
- Analyses of HIV proteases variants at the threshold of viability reveals relationships between processing efficiency and fitness.Virus evolution · 2021Article
- A single G10T polymorphism in HIV-1 subtype C Gag-SP1 regulates sensitivity to maturation inhibitors.Retrovirology · 2021Article
- Drug Design Strategies to Avoid Resistance in Direct-Acting Antivirals and Beyond.Chemical reviews · 2021Review
- Inhibiting HTLV-1 Protease: A Viable Antiviral Target.ACS chemical biology · 2021Article
- The impact of Gag non-cleavage site mutations on HIV-1 viral fitness from integrative modelling and simulations.Computational and structural biotechnology journal · 2021Article
- Structural Analysis of Potent Hybrid HIV-1 Protease Inhibitors Containing Bis-tetrahydrofuran in a Pseudosymmetric Dipeptide Isostere.Journal of medicinal chemistry · 2020Article
- Picomolar to Micromolar: Elucidating the Role of Distal Mutations in HIV-1 Protease in Conferring Drug Resistance.ACS chemical biology · 2019Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Drug resistance mutations in response to HIV-1 protease inhibitors are selected not only in the drug target but elsewhere in the viral genome, especially at the protease cleavage sites in the precursor protein Gag. To understand the molecular basis of this protease-substrate coevolution, we solved the crystal structures of drug resistant I50V/A71V HIV-1 protease with p1-p6 substrates bearing coevolved mutations. Analyses of the protease-substrate interactions reveal that compensatory coevolved mutations in the substrate do not restore interactions lost due to protease mutations, but instead establish other interactions that are not restricted to the site of mutation. Mutation of a substrate residue has distal effects on other residues' interactions as well, including through the induction of a conformational change in the protease. Additionally, molecular dynamics simulations suggest that restoration of active site dynamics is an additional constraint in the selection of coevolved mutations. Hence, protease-substrate coevolution permits mutational, structural, and dynamic changes via molecular mechanisms that involve distal effects contributing to drug resistance.
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