ArticleThe Journal of biological chemistry2010
The N348I mutation at the connection subdomain of HIV-1 reverse transcriptase decreases binding to nevirapine.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 40 citations in OpenAlex.
- Development of Human Immunodeficiency Virus Type 1 Resistance to 4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine Starting with Wild-Type or Nucleoside Reverse Transcriptase Inhibitor-Resistant Strains.Antimicrobial agents and chemotherapy · 2021Trial
- Frequent emergence of N348I in HIV-1 subtype C reverse transcriptase with failure of initial therapy reduces susceptibility to reverse-transcriptase inhibitors.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2012Trial
- Avoiding Drug Resistance in HIV Reverse Transcriptase.Chemical reviews · 2021Review
- Analysis and Molecular Determinants of HIV RNase H Cleavage Specificity at the PPT/U3 Junction.Viruses · 2021Article
- Effects of HIV-1 reverse transcriptase connection subdomain mutations on polypurine tract removal and initiation of (+)-strand DNA synthesis.Nucleic acids research · 2015Article
- Compensatory role of double mutation N348I/M184V on nevirapine binding landscape: insight from molecular dynamics simulation.The protein journal · 2014Article
- Drug resistance in non-B subtype HIV-1: impact of HIV-1 reverse transcriptase inhibitors.Viruses · 2014Review
- 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) inhibits HIV-1 reverse transcriptase with multiple mechanisms.The Journal of biological chemistry · 2014Article
- Effects of the W153L substitution in HIV reverse transcriptase on viral replication and drug resistance to multiple categories of reverse transcriptase inhibitors.Antimicrobial agents and chemotherapy · 2014Article
- Molecular dynamics study of HIV-1 RT-DNA-nevirapine complexes explains NNRTI inhibition and resistance by connection mutations.Proteins · 2014Article
- The connection domain mutation N348I in HIV-1 reverse transcriptase enhances resistance to etravirine and rilpivirine but restricts the emergence of the E138K resistance mutation by diminishing viral replication capacity.Journal of virology · 2014Article
- Hypersusceptibility mechanism of Tenofovir-resistant HIV to EFdA.Retrovirology · 2013Article
- Examining the role of the HIV-1 reverse transcriptase p51 subunit in positioning and hydrolysis of RNA/DNA hybrids.The Journal of biological chemistry · 2013Article
- Potent Inhibition of HIV-1 Reverse Transcriptase and Replication by Nonpseudoknot, "UCAA-motif" RNA Aptamers.Molecular therapy. Nucleic acids · 2013Article
- Article
- Effect of translocation defective reverse transcriptase inhibitors on the activity of N348I, a connection subdomain drug resistant HIV-1 reverse transcriptase mutant.Cellular and molecular biology (Noisy-le-Grand, France) · 2012Article
- Biochemical mechanism of HIV-1 resistance to rilpivirine.The Journal of biological chemistry · 2012Article
- Article
- HIV-1 reverse transcriptase (RT) polymorphism 172K suppresses the effect of clinically relevant drug resistance mutations to both nucleoside and non-nucleoside RT inhibitors.The Journal of biological chemistry · 2012Article
- Subunit-selective mutational analysis and tissue culture evaluations of the interactions of the E138K and M184I mutations in HIV-1 reverse transcriptase.Journal of virology · 2012Article
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
The N348I mutation at the connection subdomain of HIV-1 reverse transcriptase (RT) confers clinically significant resistance to both nucleoside and non-nucleoside RT inhibitors (NNRTIs) by mechanisms that are not well understood. We used transient kinetics to characterize the enzymatic properties of N348I RT and determine the biochemical mechanism of resistance to the NNRTI nevirapine (NVP). We demonstrate that changes distant from the NNRTI binding pocket decrease inhibitor binding (increase K(d)(-NVP)) by primarily decreasing the association rate of the inhibitor (k(on-NVP)). We characterized RTs mutated in either p66 (p66(N348I)/p51(WT)), p51 (p66(WT)/p51(N348I)), or both subunits (p66(N348I)/p51(N348I)). Mutation in either subunit caused NVP resistance during RNA-dependent and DNA-dependent DNA polymerization. Mutation in p66 alone (p66(N348I)/p51(WT)) caused NVP resistance without significantly affecting RNase H activity, whereas mutation in p51 caused NVP resistance and impaired RNase H, demonstrating that NVP resistance may occur independently from defects in RNase H function. Mutation in either subunit improved affinity for nucleic acid and enhanced processivity of DNA synthesis. Surprisingly, mutation in either subunit decreased catalytic rates (k(pol)) of p66(N348I)/p51(N348I), p66(N348I)/p51(WT), and p66(WT)/p51(N348I) without significantly affecting affinity for deoxynucleotide substrate (K(d)(-dNTP)). Hence, in addition to providing structural integrity for the heterodimer, p51 is critical for fine tuning catalytic turnover, RNase H processing, and drug resistance. In conclusion, connection subdomain mutation N348I decreases catalytic efficiency and causes in vitro resistance to NVP by decreasing 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.