ArticleBiochemistry2015
Defective hydrophobic sliding mechanism and active site expansion in HIV-1 protease drug resistant variant Gly48Thr/Leu89Met: mechanisms for the loss of saquinavir binding potency.
Article in Biochemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 37 citations in OpenAlex.
- Ligand Versatility and Resistance Mechanism of Monotherapy-Grade HIV-1 Protease Inhibitor GRL-142 Binding the Multidrug Resistant Variant p51: Insights from 1 μs MD Simulations.Journal of chemical information and modeling · 2026Article
- Predicting the Impact of Drug Resistance Mutations on Inhibitor Potency with Molecular Dynamics and Machine Learning.The journal of physical chemistry. B · 2025Article
- Subtype-Specific HIV-1 Protease and the Role of Hinge and Flap Dynamics in Drug Resistance: A Subtype C Narrative.Viruses · 2025Review
- Problematic Attributions of Entropic and Hydrophobic Effects in Drug Interactions.ACS bio & med chem Au · 2025Review
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- Computer-Aided Prediction of the Interactions of Viral Proteases with Antiviral Drugs: Antiviral Potential of Broad-Spectrum Drugs.Molecules (Basel, Switzerland) · 2023Article
- Article
- Structural and functional insights into the DNA damage-inducible protein 1 (Ddi1) from protozoa.Current research in structural biology · 2022Article
- Elasticity-Associated Functionality and Inhibition of the HIV Protease.Advances in experimental medicine and biology · 2022Article
- Deciphering Complex Mechanisms of Resistance and Loss of Potency through Coupled Molecular Dynamics and Machine Learning.Journal of chemical theory and computation · 2021Article
- Management of Antiretroviral Therapy with Boosted Protease Inhibitors-Darunavir/Ritonavir or Darunavir/Cobicistat.Biomedicines · 2021Review
- Structural Insights to Human Immunodeficiency Virus (HIV-1) Targets and Their Inhibition.Advances in experimental medicine and biology · 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
- Picomolar to Micromolar: Elucidating the Role of Distal Mutations in HIV-1 Protease in Conferring Drug Resistance.ACS chemical biology · 2019Article
- Molecular Determinants of Epistasis in HIV-1 Protease: Elucidating the Interdependence of L89V and L90M Mutations in Resistance.Biochemistry · 2019Article
- Characterizing early drug resistance-related events using geometric ensembles from HIV protease dynamics.Scientific reports · 2018Article
- Moving in the Right Direction: Protein Vibrations Steering Function.Biophysical journal · 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
- Improving Viral Protease Inhibitors to Counter Drug Resistance.Trends in microbiology · 2016Review
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
HIV drug resistance continues to emerge; consequently, there is an urgent need to develop next generation antiretroviral therapeutics.1 Here we report on the structural and kinetic effects of an HIV protease drug resistant variant with the double mutations Gly48Thr and Leu89Met (PRG48T/L89M), without the stabilizing mutations Gln7Lys, Leu33Ile, and Leu63Ile. Kinetic analyses reveal that PRG48T/L89M and PRWT share nearly identical Michaelis-Menten parameters; however, PRG48T/L89M exhibits weaker binding for IDV (41-fold), SQV (18-fold), APV (15-fold), and NFV (9-fold) relative to PRWT. A 1.9 Å resolution crystal structure was solved for PRG48T/L89M bound with saquinavir (PRG48T/L89M-SQV) and compared to the crystal structure of PRWT bound with saquinavir (PRWT-SQV). PRG48T/L89M-SQV has an enlarged active site resulting in the loss of a hydrogen bond in the S3 subsite from Gly48 to P3 of SQV, as well as less favorable hydrophobic packing interactions between P1 Phe of SQV and the S1 subsite. PRG48T/L89M-SQV assumes a more open conformation relative to PRWT-SQV, as illustrated by the downward displacement of the fulcrum and elbows and weaker interatomic flap interactions. We also show that the Leu89Met mutation disrupts the hydrophobic sliding mechanism by causing a redistribution of van der Waals interactions in the hydrophobic core in PRG48T/L89M-SQV. Our mechanism for PRG48T/L89M-SQV drug resistance proposes that a defective hydrophobic sliding mechanism results in modified conformational dynamics of the protease. As a consequence, the protease is unable to achieve a fully closed conformation that results in an expanded active site and weaker inhibitor binding.
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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.