ArticleJournal of virology2004
Structural basis for coevolution of a human immunodeficiency virus type 1 nucleocapsid-p1 cleavage site with a V82A drug-resistant mutation in viral protease.
Article in Journal of virology, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed, 101 citations in OpenAlex.
- Gag mutations can impact virological response to dual-boosted protease inhibitor combinations in antiretroviral-naïve HIV-infected patients.Antimicrobial agents and chemotherapy · 2010Trial
- Subtype-Specific HIV-1 Protease and the Role of Hinge and Flap Dynamics in Drug Resistance: A Subtype C Narrative.Viruses · 2025Review
- FMO-guided design of darunavir analogs as HIV-1 protease inhibitors.Scientific reports · 2024Article
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- CHARMM-GUI Implicit Solvent Modeler for Various Generalized Born Models in Different Simulation Programs.The journal of physical chemistry. B · 2022Article
- Covariation of viral recombination with single nucleotide variants during virus evolution revealed by CoVaMa.Nucleic acids research · 2022Article
- Potential Resistance of SARS-CoV-2 Main Protease (Mpro) against Protease Inhibitors: Lessons Learned from HIV-1 Protease.International journal of molecular sciences · 2022Review
- Elasticity-Associated Functionality and Inhibition of the HIV Protease.Advances in experimental medicine and biology · 2022Article
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- Amino-acid inserts of HIV-1 capsid (CA) induce CA degradation and abrogate viral infectivity: Insights for the dynamics and mechanisms of HIV-1 CA decomposition.Scientific reports · 2019Article
- Highly Drug-Resistant HIV-1 Protease Mutant PRS17 Shows Enhanced Binding to Substrate Analogues.ACS omega · 2019Article
- AnACS catalysis · 2019Article
- Selection analyses of paired HIV-1 gag and gp41 sequences obtained before and after antiretroviral therapy.Scientific data · 2018Article
- Evolution of gag and gp41 in Patients Receiving Ritonavir-Boosted Protease Inhibitors.Scientific reports · 2017Article
- Improving Viral Protease Inhibitors to Counter Drug Resistance.Trends in microbiology · 2016Review
- Elucidation of the Molecular Mechanism Driving Duplication of the HIV-1 PTAP Late Domain.Journal of virology · 2016Article
- Modulation of HIV protease flexibility by the T80N mutation.Proteins · 2015Article
- Function-based mutation-resistant synthetic signaling device activated by HIV-1 proteolysis.ACS synthetic biology · 2015Article
- Drug-resistant HIV-1 protease regains functional dynamics through cleavage site coevolution.Evolutionary applications · 2015Article
- HIV-1 protease-substrate coevolution in nelfinavir resistance.Journal of virology · 2014Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Maturation of human immunodeficiency virus (HIV) depends on the processing of Gag and Pol polyproteins by the viral protease, making this enzyme a prime target for anti-HIV therapy. Among the protease substrates, the nucleocapsid-p1 (NC-p1) sequence is the least homologous, and its cleavage is the rate-determining step in viral maturation. In the other substrates of HIV-1 protease, P1 is usually either a hydrophobic or an aromatic residue, and P2 is usually a branched residue. NC-p1, however, contains Asn at P1 and Ala at P2. In response to the V82A drug-resistant protease mutation, the P2 alanine of NC-p1 mutates to valine (AP2V). To provide a structural rationale for HIV-1 protease binding to the NC-p1 cleavage site, we solved the crystal structures of inactive (D25N) WT and V82A HIV-1 proteases in complex with their respective WT and AP2V mutant NC-p1 substrates. Overall, the WT NC-p1 peptide binds HIV-1 protease less optimally than the AP2V mutant, as indicated by the presence of fewer hydrogen bonds and fewer van der Waals contacts. AlaP2 does not fill the P2 pocket completely; PheP1' makes van der Waals interactions with Val82 that are lost with the V82A protease mutation. This loss is compensated by the AP2V mutation, which reorients the peptide to a conformation more similar to that observed in other substrate-protease complexes. Thus, the mutant substrate not only binds the mutant protease more optimally but also reveals the interdependency between the P1' and P2 substrate sites. This structural interdependency results from coevolution of the substrate with the viral protease.
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