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

Autor: Vannajan Sanghiran Lee, Somphot Saoin, Sawitree Nangola, Warachai Praditwongwan, Saw See Hong, Pierre Boulanger, Phimonphan Chuankhayan, Philippe Minard, Chun-Jung Chen, Chatchai Tayapiwatana, Tanchanok Wisitponchai
Přispěvatelé: Infections Virales et Pathologie Comparée - UMR 754 (IVPC), Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Rétrovirus et Pathologie Comparée (RPC), Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL), National Research University project under the Thailand's Office of the Commission on Higher Education, National Sciences and the Technology Development Agency at the Faculty of Associated Medical Sciences, Chiang Mai University, Thailand Research Fund, French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS) [11344/2011-2013], University of Malaya for UMRG [RP002-2012D], University of Malaya for FRGS [FP008-2012A], National Science Council [101-2628-B-213-001-MY4 ], NSRRC [1013RSB02]
Rok vydání: 2013
Předmět:
Models
Molecular
Molecular model
Protein Conformation
viruses
[SDV]Life Sciences [q-bio]
Sequence Homology
HIV Infections
Plasma protein binding
Crystallography
X-Ray
Protein structure
Models
Drug Discovery
Protein Interaction Mapping
Ankyrin
Peptide sequence
chemistry.chemical_classification
0303 health sciences
Crystallography
Recombinant Proteins/chemistry/genetics/metabolism
030302 biochemistry & molecular biology
Ankyrins/*pharmacology
Antiviral Agents/*pharmacology
Recombinant Proteins
3. Good health
Computer Science Applications
Cell biology
Amino Acid
Capsid
Protein Binding
Ankyrins
Protein Structure
Mutation/genetics
Sequence analysis
Molecular Sequence Data
Enzyme-Linked Immunosorbent Assay
Biology
Antiviral Agents
03 medical and health sciences
Humans
Homology modeling
Capsid Proteins/*chemistry/genetics/*metabolism
Amino Acid Sequence
Physical and Theoretical Chemistry
HIV Infections/drug therapy/virology
HIV-1/*drug effects/growth & development
030304 developmental biology
Sequence Homology
Amino Acid
Virus Assembly
Molecular
Molecular biology
Protein Structure
Tertiary
chemistry
Mutation
X-Ray
HIV-1
Capsid Proteins
Tertiary
Zdroj: JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 2014, 28 (8), pp.869-84. ⟨10.1007/s10822-014-9772-9⟩
ISSN: 1573-4951
DOI: 10.1007/s10822-014-9772-9⟩
Popis: International audience; 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 A 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.
Databáze: OpenAIRE
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