ArticleThe Journal of biological chemistry2016
Effects of Hinge-region Natural Polymorphisms on Human Immunodeficiency Virus-Type 1 Protease Structure, Dynamics, and Drug Pressure Evolution.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 27 citations in OpenAlex.
- Allophycocyanin inhibits HIV-1 gp120 and reverse transcriptase through enthalpy-driven binding and antioxidative protection: integrative computational and experimental insights.Scientific reports · 2026Article
- Predicting the Impact of Drug Resistance Mutations on Inhibitor Potency with Molecular Dynamics and Machine Learning.The journal of physical chemistry. B · 2025Article
- Premature Activation of the HIV-1 Protease Is Influenced by Polymorphisms in the Hinge Region.Viruses · 2024Article
- Accelerating reliable multiscale quantum refinement of protein-drug systems enabled by machine learning.Nature communications · 2024Article
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- Mitochondrial resilience and antioxidant defence against HIV-1: unveiling the power ofFrontiers in microbiology · 2024Article
- HIV-1 protease with 10 lopinavir and darunavir resistance mutations exhibits altered inhibition, structural rearrangements and extreme dynamics.Journal of molecular graphics & modelling · 2022Article
- Beyond structure: Deciphering site-specific dynamics in proteins from double histidine-based EPR measurements.Protein science : a publication of the Protein Society · 2022Article
- Predicting robotic-assisted total knee arthroplasty operating time : benefits of machine-learning and 3D patient-specific data.Bone & joint open · 2022Article
- HIV-1 Protease and Reverse Transcriptase Inhibitory Activities ofPharmaceuticals (Basel, Switzerland) · 2021Article
- Crystal structures of inhibitor complexes of M-PMV protease with visible flap loops.Protein science : a publication of the Protein Society · 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
- HIV-1 protease and reverse transcriptase inhibition by tiger milk mushroom (Journal of traditional and complementary medicine · 2020Article
- Energetics of Flap Opening in HIV-1 Protease: String Method Calculations.The journal of physical chemistry. B · 2019Article
- Characterizing early drug resistance-related events using geometric ensembles from HIV protease dynamics.Scientific reports · 2018Article
Corrections and comments
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
Multidrug resistance to current Food and Drug Administration-approved HIV-1 protease (PR) inhibitors drives the need to understand the fundamental mechanisms of how drug pressure-selected mutations, which are oftentimes natural polymorphisms, elicit their effect on enzyme function and resistance. Here, the impacts of the hinge-region natural polymorphism at residue 35, glutamate to aspartate (E35D), alone and in conjunction with residue 57, arginine to lysine (R57K), are characterized with the goal of understanding how altered salt bridge interactions between the hinge and flap regions are associated with changes in structure, motional dynamics, conformational sampling, kinetic parameters, and inhibitor affinity. The combined results reveal that the single E35D substitution leads to diminished salt bridge interactions between residues 35 and 57 and gives rise to the stabilization of open-like conformational states with overall increased backbone dynamics. In HIV-1 PR constructs where sites 35 and 57 are both mutated (e.g. E35D and R57K), x-ray structures reveal an altered network of interactions that replace the salt bridge thus stabilizing the structural integrity between the flap and hinge regions. Despite the altered conformational sampling and dynamics when the salt bridge is disrupted, enzyme kinetic parameters and inhibition constants are similar to those obtained for subtype B PR. Results demonstrate that these hinge-region natural polymorphisms, which may arise as drug pressure secondary mutations, alter protein dynamics and the conformational landscape, which are important thermodynamic parameters to consider for development of inhibitors that target for non-subtype B PR.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.