ArticleJournal of computer-aided molecular design2014
Crystal structure of an antiviral ankyrin targeting the HIV-1 capsid and molecular modeling of the ankyrin-capsid complex.
Article in Journal of computer-aided molecular design, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 11 citations in OpenAlex.
- Dimeric Ankyrin with Inverted Module Promotes Bifunctional Property in Capturing Capsid to Impede HIV-1 Replication.International journal of molecular sciences · 2023Article
- Review
- Performance of Affinity-Improved DARPin Targeting HIV Capsid Domain in Interference of Viral Progeny Production.Biomolecules · 2021Article
- Protein-Protein Interactions: Insight from Molecular Dynamics Simulations and Nanoparticle Tracking Analysis.Molecules (Basel, Switzerland) · 2021Article
- Article
- AnkPlex: algorithmic structure for refinement of near-native ankyrin-protein docking.BMC bioinformatics · 2017Article
- Combined Antiviral Therapy Using Designed Molecular Scaffolds Targeting Two Distinct Viral Functions, HIV-1 Genome Integration and Capsid Assembly.Molecular therapy. Nucleic acids · 2015Article
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Authors and funding
11 authors at 7 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Ankyrins are cellular repeat proteins, which can be genetically modified to randomize amino-acid residues located at defined positions in each repeat unit, and thus create a potential binding surface adaptable to macromolecular ligands. From a phage-display library of artificial ankyrins, we have isolated Ank(GAG)1D4, a trimodular ankyrin which binds to the HIV-1 capsid protein N-terminal domain (NTD(CA)) and has an antiviral effect at the late steps of the virus life cycle. In this study, the determinants of the Ank(GAG)1D4-NTD(CA) interaction were analyzed using peptide scanning in competition ELISA, capsid mutagenesis, ankyrin crystallography and molecular modeling. We determined the Ank(GAG)1D4 structure at 2.2 Å resolution, and used the crystal structure in molecular docking with a homology model of HIV-1 capsid. Our results indicated that NTD(CA) alpha-helices H1 and H7 could mediate the formation of the capsid-Ank(GAG)1D4 binary complex, but the interaction involving H7 was predicted to be more stable than with H1. Arginine-18 (R18) in H1, and R132 and R143 in H7 were found to be the key players of the Ank(GAG)1D4-NTD(CA) interaction. This was confirmed by R-to-A mutagenesis of NTD(CA), and by sequence analysis of trimodular ankyrins negative for capsid binding. In Ank(GAG)1D4, major interactors common to H1 and H7 were found to be S45, Y56, R89, K122 and K123. Collectively, our ankyrin-capsid binding analysis implied a significant degree of flexibility within the NTD(CA) domain of the HIV-1 capsid protein, and provided some clues for the design of new antivirals targeting the capsid protein and viral assembly.
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