Journal of Computer-Aided Molecular Design

, Volume 28, Issue 8, pp 869–884 | Cite as

Crystal structure of an antiviral ankyrin targeting the HIV-1 capsid and molecular modeling of the ankyrin-capsid complex

  • Warachai Praditwongwan
  • Phimonphan Chuankhayan
  • Somphot Saoin
  • Tanchanok Wisitponchai
  • Vannajan Sanghiran Lee
  • Sawitree Nangola
  • Saw See Hong
  • Philippe Minard
  • Pierre Boulanger
  • Chun-Jung Chen
  • Chatchai Tayapiwatana
Article

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 AnkGAG1D4, a trimodular ankyrin which binds to the HIV-1 capsid protein N-terminal domain (NTDCA) and has an antiviral effect at the late steps of the virus life cycle. In this study, the determinants of the AnkGAG1D4-NTDCA interaction were analyzed using peptide scanning in competition ELISA, capsid mutagenesis, ankyrin crystallography and molecular modeling. We determined the AnkGAG1D4 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 NTDCA alpha-helices H1 and H7 could mediate the formation of the capsid-AnkGAG1D4 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 AnkGAG1D4-NTDCA interaction. This was confirmed by R-to-A mutagenesis of NTDCA, and by sequence analysis of trimodular ankyrins negative for capsid binding. In AnkGAG1D4, 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 NTDCA domain of the HIV-1 capsid protein, and provided some clues for the design of new antivirals targeting the capsid protein and viral assembly.

Keywords

HIV-1 CA protein Ankyrins Molecular docking Modeling Viral assembly Antivirals 

Supplementary material

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Supplementary material 8 (PDF 66 kb)

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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Warachai Praditwongwan
    • 1
    • 2
  • Phimonphan Chuankhayan
    • 3
  • Somphot Saoin
    • 1
    • 2
  • Tanchanok Wisitponchai
    • 6
  • Vannajan Sanghiran Lee
    • 7
    • 8
  • Sawitree Nangola
    • 9
  • Saw See Hong
    • 10
    • 11
    • 12
  • Philippe Minard
    • 13
  • Pierre Boulanger
    • 10
    • 11
  • Chun-Jung Chen
    • 3
    • 4
    • 5
  • Chatchai Tayapiwatana
    • 1
    • 2
  1. 1.Division of Clinical Immunology, Department of Medical Technology, Faculty of Associated Medical SciencesChiang Mai UniversityChiang MaiThailand
  2. 2.Biomedical Technology Research Unit, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency at the Faculty of Associated Medical SciencesChiang Mai UniversityChiang MaiThailand
  3. 3.Life Science Group, Scientific Research DivisionNational Synchrotron Radiation Research CenterHsinchuTaiwan
  4. 4.Department of PhysicsNational Tsing Hua UniversityHsinchuTaiwan
  5. 5.Institute of BiotechnologyNational Cheng Kung UniversityTainanTaiwan
  6. 6.Biomedical Engineering Center, Faculty of EngineeringChiang Mai UniversityChiang MaiThailand
  7. 7.Computational Simulation Modelling Laboratory (CSML), Department of Chemistry and Center of Excellence for Innovation in Chemistry and Materials Science Research CenterFaculty of Science, Chiang Mai UniversityChiang MaiThailand
  8. 8.Department of Chemistry, Faculty of ScienceUniversity of MalayaKuala LumpurMalaysia
  9. 9.Division of Clinical Immunology and Transfusion Sciences, Department of Medical Technology, School of Allied Health SciencesUniversity of PhayaoPhayaoThailand
  10. 10.Laboratory of Retrovirus and Comparative Pathology, UMR-754University Lyon 1Lyon Cedex 07France
  11. 11.UMR-754, Retrovirus and Comparative PathologyINRALyon Cedex 07France
  12. 12.Institut National de la Santé et de la Recherche Médicale (INSERM)ParisFrance
  13. 13.Institut de Biochimie et de Biophysique Moléculaire et Cellulaire (IBBMC) UMR-8619Université de Paris-Sud et CNRSOrsay CedexFrance

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