ArticleBiochemistry2013
Elucidating a relationship between conformational sampling and drug resistance in HIV-1 protease.
Article in Biochemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 35 citations in OpenAlex.
- Article
- Identification of Aloe-derived natural products as prospective lead scaffolds for SARS-CoV-2 main protease (MBioorganic & medicinal chemistry letters · 2022Article
- Acquired HIV-1 Protease Conformational Flexibility Associated with Lopinavir Failure May Shape the Outcome of Darunavir Therapy after Antiretroviral Therapy Switch.Biomolecules · 2021Article
- Cleavage of TANK-Binding Kinase 1 by HIV-1 Protease Triggers Viral Innate Immune Evasion.Frontiers in microbiology · 2021Article
- Viewing rare conformations of the βProceedings of the National Academy of Sciences of the United States of America · 2020Article
- 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
- Room Temperature Neutron Crystallography of Drug Resistant HIV-1 Protease Uncovers Limitations of X-ray Structural Analysis at 100 K.Journal of medicinal chemistry · 2017Article
- Effects of Hinge-region Natural Polymorphisms on Human Immunodeficiency Virus-Type 1 Protease Structure, Dynamics, and Drug Pressure Evolution.The Journal of biological chemistry · 2016Article
- A Bayesian approach to quantifying uncertainty from experimental noise in DEER spectroscopy.Journal of magnetic resonance (San Diego, Calif. : 1997) · 2016Article
- Improving Viral Protease Inhibitors to Counter Drug Resistance.Trends in microbiology · 2016Review
- Pulsed EPR characterization of HIV-1 protease conformational sampling and inhibitor-induced population shifts.Physical chemistry chemical physics : PCCP · 2016Article
- Spin labeling and Double Electron-Electron Resonance (DEER) to Deconstruct Conformational Ensembles of HIV Protease.Methods in enzymology · 2015Article
- Highly resistant HIV-1 proteases and strategies for their inhibition.Future medicinal chemistry · 2015Review
- Structural basis and distal effects of Gag substrate coevolution in drug resistance to HIV-1 protease.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Effects of PRE and POST therapy drug-pressure selected mutations on HIV-1 protease conformational sampling.FEBS letters · 2014Article
- Drug Resistance Mutations Alter Dynamics of Inhibitor-Bound HIV-1 Protease.Journal of chemical theory and computation · 2014Article
- The role of select subtype polymorphisms on HIV-1 protease conformational sampling and dynamics.The Journal of biological chemistry · 2014Article
- Mapping protein conformational heterogeneity under pressure with site-directed spin labeling and double electron-electron resonance.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Enzyme targets in rapidly replicating systems, such as retroviruses, commonly respond to drug-selective pressure with mutations arising in the active site pocket that limit inhibitor effectiveness by introducing steric hindrance or by eliminating essential molecular interactions. However, these primary mutations are disposed to compromising pathogenic fitness. Emerging secondary mutations, which are often found outside of the binding cavity, may or can restore fitness while maintaining drug resistance. The accumulated drug pressure selected mutations could have an indirect effect in the development of resistance, such as altering protein flexibility or the dynamics of protein-ligand interactions. Here, we show that accumulation of mutations in a drug-resistant HIV-1 protease (HIV-1 PR) variant, D30N/M36I/A71V, changes the fractional occupancy of the equilibrium conformational sampling ensemble. Correlations are made among populations of the conformational states, namely, closed-like, semiopen, and open-like, with inhibition constants, as well as kinetic parameters. Mutations that stabilize a closed-like conformation correlate with enzymes of lowered activity and with higher affinity for inhibitors, which is corroborated by a further increase in the fractional occupancy of the closed state upon addition of inhibitor or substrate-mimic. Cross-resistance is found to correlate with combinations of mutations that increase the population of the open-like conformations at the expense of the closed-like state while retaining native-like occupancy of the semiopen population. These correlations suggest that at least three states are required in the conformational sampling model to establish the emergence of drug resistance in HIV-1 PR. More importantly, these results shed light on a possible mechanism whereby mutations combine to impart drug resistance while maintaining catalytic activity.
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