ArticleRetrovirology2014
The mechanism of H171T resistance reveals the importance of Nδ-protonated His171 for the binding of allosteric inhibitor BI-D to HIV-1 integrase.
Article in Retrovirology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 41 citations in OpenAlex.
- Article
- The structural and mechanistic bases for the viral resistance to allosteric HIV-1 integrase inhibitor pirmitegravir.bioRxiv : the preprint server for biology · 2024Article
- The Drug-Induced Interface That Drives HIV-1 Integrase Hypermultimerization and Loss of Function.mBio · 2023Article
- Article
- Multimodal Functionalities of HIV-1 Integrase.Viruses · 2022Review
- Structure-based virtual screening workflow to identify antivirals targeting HIV-1 capsid.Journal of computer-aided molecular design · 2022Article
- Article
- Article
- Retroviral integrase: Structure, mechanism, and inhibition.The Enzymes · 2021Article
- Integrase-RNA interactions underscore the critical role of integrase in HIV-1 virion morphogenesis.eLife · 2020Article
- A Conformational Escape Reaction of HIV-1 against an Allosteric Integrase Inhibitor.Journal of virology · 2020Article
- Combining Alchemical Transformation with a Physical Pathway to Accelerate Absolute Binding Free Energy Calculations of Charged Ligands to Enclosed Binding Sites.Journal of chemical theory and computation · 2020Article
- Ligand Binding Thermodynamic Cycles: Hysteresis, the Locally Weighted Histogram Analysis Method, and the Overlapping States Matrix.Journal of chemical theory and computation · 2020Article
- Multifaceted HIV integrase functionalities and therapeutic strategies for their inhibition.The Journal of biological chemistry · 2019Review
- Structure-Guided Identification of Resistance Breaking Antimalarial N‑Myristoyltransferase Inhibitors.Cell chemical biology · 2019Article
- HIV-1 integrase tetramers are the antiviral target of pyridine-based allosteric integrase inhibitors.eLife · 2019Article
- An Isoquinoline Scaffold as a Novel Class of Allosteric HIV-1 Integrase Inhibitors.ACS medicinal chemistry letters · 2019Article
- Synthesis and Evaluation of Aryl Quinolines as HIV-1 Integrase Multimerization Inhibitors.ACS medicinal chemistry letters · 2018Article
- Comparing alchemical and physical pathway methods for computing the absolute binding free energy of charged ligands.Physical chemistry chemical physics : PCCP · 2018Article
- Structure-function analyses unravel distinct effects of allosteric inhibitors of HIV-1 integrase on viral maturation and integration.The Journal of biological chemistry · 2018Article
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Authors and funding
15 authors at 5 institutions in 1 country.
Funding
Abstract
backgroundAllosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are an important new class of anti-HIV-1 agents. ALLINIs bind at the IN catalytic core domain (CCD) dimer interface occupying the principal binding pocket of its cellular cofactor LEDGF/p75. Consequently, ALLINIs inhibit HIV-1 IN interaction with LEDGF/p75 as well as promote aberrant IN multimerization. Selection of viral strains emerging under the inhibitor pressure has revealed mutations at the IN dimer interface near the inhibitor binding site.
resultsWe have investigated the effects of one of the most prevalent substitutions, H171T IN, selected under increasing pressure of ALLINI BI-D. Virus containing the H171T IN substitution exhibited an ~68-fold resistance to BI-D treatment in infected cells. These results correlated with ~84-fold reduced affinity for BI-D binding to recombinant H171T IN CCD protein compared to its wild type (WT) counterpart. However, the H171T IN substitution only modestly affected IN-LEDGF/p75 binding and allowed HIV-1 containing this substitution to replicate at near WT levels. The x-ray crystal structures of BI-D binding to WT and H171T IN CCD dimers coupled with binding free energy calculations revealed the importance of the Nδ- protonated imidazole group of His171 for hydrogen bonding to the BI-D tert-butoxy ether oxygen and establishing electrostatic interactions with the inhibitor carboxylic acid, whereas these interactions were compromised upon substitution to Thr171.
conclusionsOur findings reveal a distinct mechanism of resistance for the H171T IN mutation to ALLINI BI-D and indicate a previously undescribed role of the His171 side chain for binding the inhibitor.
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