Zika Virus Methyltransferase: Structure and Functions for Drug Design Perspectives
| Autor: | Karine Barral, Françoise Debart, Baptiste Martin, Bruno Canard, Jean-Jacques Vasseur, Etienne Decroly, Bruno Coutard, Wahiba Aouadi, Barbara Selisko, Miguel Ortiz Lombardia, Julie Lichière, Jean-Claude Guillemot |
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| Přispěvatelé: | Architecture et fonction des macromolécules biologiques (AFMB), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Information génomique et structurale (IGS), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Architecture et fonction des macromolécules biologiques ( AFMB ), Centre National de la Recherche Scientifique ( CNRS ) -Aix Marseille Université ( AMU ) -Institut National de la Recherche Agronomique ( INRA ), Centre de Recherche en Cancérologie de Marseille ( CRCM ), Aix Marseille Université ( AMU ) -Institut Paoli-Calmettes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Information génomique et structurale ( IGS ), Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] ( IBMM ), Ecole Nationale Supérieure de Chimie de Montpellier ( ENSCM ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ) |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Models
Molecular 0301 basic medicine MESH : Escherichia coli MESH : Drug Design Methyltransferase viruses MESH : Allosteric Site MESH: Catalytic Domain Protein structure function Viral Nonstructural Proteins Dengue virus MESH: Drug Design Crystallography X-Ray medicine.disease_cause Zika virus flavivirus Catalytic Domain Transferase MESH: Allosteric Site MESH : Viral Nonstructural Proteins MESH : Methyltransferases [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry Molecular Biology/Structural Biology [q-bio.BM] MESH: Escherichia coli MESH : Catalytic Domain MESH : Protein Binding Genome Replication and Regulation of Viral Gene Expression MESH : Antiviral Agents 3. Good health Flavivirus [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biomolecules [q-bio.BM] [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology Allosteric Site MESH: Models Molecular Protein Binding MESH: Antiviral Agents MESH : Models Molecular 030106 microbiology Immunology MESH: Zika Virus Biology Antiviral Agents [ SDV.MP.VIR ] Life Sciences [q-bio]/Microbiology and Parasitology/Virology Microbiology 03 medical and health sciences Virology MESH: Methyltransferases Escherichia coli medicine MESH : Hydrogen Bonding MESH: Protein Binding MESH: Hydrogen Bonding Binding site RNA protein structure-function Hydrogen Bonding Methyltransferases MESH : Zika Virus biology.organism_classification MESH: Crystallography X-Ray Molecular biology 030104 developmental biology Viral replication RNA processing Drug Design Insect Science MESH: Viral Nonstructural Proteins methyltransferase MESH : Crystallography X-Ray [ SDV.BBM.BS ] Life Sciences [q-bio]/Biochemistry Molecular Biology/Biomolecules [q-bio.BM] |
| Zdroj: | Journal of Virology Journal of Virology, American Society for Microbiology, 2017, 91 (5), pp.2202-2218. ⟨10.1128/JVI.02202-16⟩ Journal of Virology, 2017, 91 (5), pp.2202-2218. ⟨10.1128/JVI.02202-16⟩ Journal of Virology, American Society for Microbiology, 2017, 91 (5), pp.2202-2218. 〈10.1128/JVI.02202-16〉 |
| ISSN: | 0022-538X 1098-5514 |
| Popis: | The Flavivirus Zika virus (ZIKV) is the causal agent of neurological disorders like microcephaly in newborns or Guillain-Barre syndrome. Its NS5 protein embeds a methyltransferase (MTase) domain involved in the formation of the viral mRNA cap. We investigated the structural and functional properties of the ZIKV MTase. We show that the ZIKV MTase can methylate RNA cap structures at the N-7 position of the cap, and at the 2′-O position on the ribose of the first nucleotide, yielding a cap-1 structure. In addition, the ZIKV MTase methylates the ribose 2′-O position of internal adenosines of RNA substrates. The crystal structure of the ZIKV MTase determined at a 2.01-Å resolution reveals a crystallographic homodimer. One chain is bound to the methyl donor ( S -adenosyl- l -methionine [SAM]) and shows a high structural similarity to the dengue virus (DENV) MTase. The second chain lacks SAM and displays conformational changes in the αX α-helix contributing to the SAM and RNA binding. These conformational modifications reveal a possible molecular mechanism of the enzymatic turnover involving a conserved Ser/Arg motif. In the second chain, the SAM binding site accommodates a sulfate close to a glycerol that could serve as a basis for structure-based drug design. In addition, compounds known to inhibit the DENV MTase show similar inhibition potency on the ZIKV MTase. Altogether these results contribute to a better understanding of the ZIKV MTase, a central player in viral replication and host innate immune response, and lay the basis for the development of potential antiviral drugs. IMPORTANCE The Zika virus (ZIKV) is associated with microcephaly in newborns, and other neurological disorders such as Guillain-Barre syndrome. It is urgent to develop antiviral strategies inhibiting the viral replication. The ZIKV NS5 embeds a methyltransferase involved in the viral mRNA capping process, which is essential for viral replication and control of virus detection by innate immune mechanisms. We demonstrate that the ZIKV methyltransferase methylates the mRNA cap and adenosines located in RNA sequences. The structure of ZIKV methyltransferase shows high structural similarities to the dengue virus methyltransferase, but conformational specificities highlight the role of a conserved Ser/Arg motif, which participates in RNA and SAM recognition during the reaction turnover. In addition, the SAM binding site accommodates a sulfate and a glycerol, offering structural information to initiate structure-based drug design. Altogether, these results contribute to a better understanding of the Flavivirus methyltransferases, which are central players in the virus replication. |
| Databáze: | OpenAIRE |
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