Three-dimensional Structure of Influenza A N9 Neuraminidase and Its Complex with the Inhibitor 2-Deoxy 2,3-Dehydro- N -Acetyl Neuraminic Acid
Identifieur interne : 001794 ( Istex/Curation ); précédent : 001793; suivant : 001795Three-dimensional Structure of Influenza A N9 Neuraminidase and Its Complex with the Inhibitor 2-Deoxy 2,3-Dehydro- N -Acetyl Neuraminic Acid
Auteurs : P. Bossart-Whitaker [Australie] ; M. Carson [Australie] ; Y. S. Babu [Australie] ; C. D. Smith [Australie] ; W. G. Laver [Australie] ; Gillian M. Air [Australie]Source :
- Journal of Molecular Biology [ 0022-2836 ] ; 1993.
English descriptors
Abstract
Abstract: We present here the three-dimensional structure of neuraminidase (E.C. 3.2.1.18) from influenza virus A/Tern/Australia/G70c/75 (N9), determined by the method of multiple isomorphous replacement, and the structure of the neuraminidase complexed with an inhibitor, 2-deoxy-2,3-dehydro-N-acetyl neuraminic acid (DANA). Native and inhibitor complex crystals are isomorphous and belong to space group I432 with unit cell dimensions of 183·78 Å. The native enzyme structure and the inhibitor complex structure have been refined at 2·5 Å and 2·8 Å resolution, respectively, with crystallographic R-factor values of 0·193 for the native enzyme, and 0·179 for the inhibitor complex. The current enzyme model includes 387 amino acid residues which comprise the asymmetric unit. The root-mean-square deviation from ideal values is 0·013 Å for bond lengths and 1·6° for bond angles. The neuraminidase (NA), as proteolytically cleaved from the virus, retains full enzymatic and antigenic activity, and is a box-shaped tetramer with edge lengths of 90 Å and a maximal depth of 60 Å. The NA tetramers are composed of crystallographically equivalent monomers related by circular 4-fold symmetry. Each monomer folds into six antiparallel β-sheets of four strands. The secondary structure composition is 500% β-sheet. The remaining 50% of the residues form 24 strand connecting loops or turns. One of the loops contains a small α-helix. The structure of the complex of NA with DANA, a transition state analog, has enabled us to identify and characterize the site of enzyme catalysis. The center of mass of bound inhibitor is 32 Å from the 4-fold axis of the tetramer, lodged at the end of a shallow crater of diameter 16 Å with a depth of 8 to 10 Å. There are 12 amino acid residues that directly bind DANA, with a further six conserved amino acids lining the active site pocket. The neuraminidase inhibitor complex provides a three-dimensional model which will be used to further the understanding of enzymatic hydrolysis and aid the design of specific, anti-neuraminidase antiviral compounds.
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DOI: 10.1006/jmbi.1993.1461
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Bossart-Whitaker</name><affiliation wicri:level="1"><mods:affiliation>Department of Microbiology and Center for Macromolecular Crystallography University of Alabama at Birmingham Birmingham, AL 35294, U.S.A.; Biocryst Pharmaceuticals Inc. 2190 Parkway Lake Drive, Birmingham, AL 35244, U.S.A. and John Curtin School of Medical Research The Australian National University, Canberra, Australia</mods:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Microbiology and Center for Macromolecular Crystallography University of Alabama at Birmingham Birmingham, AL 35294, U.S.A.; Biocryst Pharmaceuticals Inc. 2190 Parkway Lake Drive, Birmingham, AL 35244, U.S.A. and John Curtin School of Medical Research The Australian National University, Canberra</wicri:regionArea></affiliation></author><author><name sortKey="Carson, M" sort="Carson, M" uniqKey="Carson M" first="M." last="Carson">M. 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Smith</name><affiliation wicri:level="1"><mods:affiliation>Department of Microbiology and Center for Macromolecular Crystallography University of Alabama at Birmingham Birmingham, AL 35294, U.S.A.; Biocryst Pharmaceuticals Inc. 2190 Parkway Lake Drive, Birmingham, AL 35244, U.S.A. and John Curtin School of Medical Research The Australian National University, Canberra, Australia</mods:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Microbiology and Center for Macromolecular Crystallography University of Alabama at Birmingham Birmingham, AL 35294, U.S.A.; Biocryst Pharmaceuticals Inc. 2190 Parkway Lake Drive, Birmingham, AL 35244, U.S.A. and John Curtin School of Medical Research The Australian National University, Canberra</wicri:regionArea></affiliation></author><author><name sortKey="Laver, W G" sort="Laver, W G" uniqKey="Laver W" first="W. G." last="Laver">W. G. Laver</name><affiliation wicri:level="1"><mods:affiliation>Department of Microbiology and Center for Macromolecular Crystallography University of Alabama at Birmingham Birmingham, AL 35294, U.S.A.; Biocryst Pharmaceuticals Inc. 2190 Parkway Lake Drive, Birmingham, AL 35244, U.S.A. and John Curtin School of Medical Research The Australian National University, Canberra, Australia</mods:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Microbiology and Center for Macromolecular Crystallography University of Alabama at Birmingham Birmingham, AL 35294, U.S.A.; Biocryst Pharmaceuticals Inc. 2190 Parkway Lake Drive, Birmingham, AL 35244, U.S.A. and John Curtin School of Medical Research The Australian National University, Canberra</wicri:regionArea></affiliation></author><author><name sortKey="Air, Gillian M" sort="Air, Gillian M" uniqKey="Air G" first="Gillian M." last="Air">Gillian M. Air</name><affiliation wicri:level="1"><mods:affiliation>Department of Microbiology and Center for Macromolecular Crystallography University of Alabama at Birmingham Birmingham, AL 35294, U.S.A.; Biocryst Pharmaceuticals Inc. 2190 Parkway Lake Drive, Birmingham, AL 35244, U.S.A. and John Curtin School of Medical Research The Australian National University, Canberra, Australia</mods:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Microbiology and Center for Macromolecular Crystallography University of Alabama at Birmingham Birmingham, AL 35294, U.S.A.; Biocryst Pharmaceuticals Inc. 2190 Parkway Lake Drive, Birmingham, AL 35244, U.S.A. and John Curtin School of Medical Research The Australian National University, Canberra</wicri:regionArea></affiliation></author></analytic><monogr></monogr><series><title level="j">Journal of Molecular Biology</title><title level="j" type="abbrev">YJMBI</title><idno type="ISSN">0022-2836</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1993">1993</date><biblScope unit="volume">232</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="1069">1069</biblScope><biblScope unit="page" to="1083">1083</biblScope></imprint><idno type="ISSN">0022-2836</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-2836</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>MIR structure</term><term>influenza virus</term><term>inhibitor complex</term><term>neuraminidase</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Abstract: We present here the three-dimensional structure of neuraminidase (E.C. 3.2.1.18) from influenza virus A/Tern/Australia/G70c/75 (N9), determined by the method of multiple isomorphous replacement, and the structure of the neuraminidase complexed with an inhibitor, 2-deoxy-2,3-dehydro-N-acetyl neuraminic acid (DANA). Native and inhibitor complex crystals are isomorphous and belong to space group I432 with unit cell dimensions of 183·78 Å. The native enzyme structure and the inhibitor complex structure have been refined at 2·5 Å and 2·8 Å resolution, respectively, with crystallographic R-factor values of 0·193 for the native enzyme, and 0·179 for the inhibitor complex. The current enzyme model includes 387 amino acid residues which comprise the asymmetric unit. The root-mean-square deviation from ideal values is 0·013 Å for bond lengths and 1·6° for bond angles. The neuraminidase (NA), as proteolytically cleaved from the virus, retains full enzymatic and antigenic activity, and is a box-shaped tetramer with edge lengths of 90 Å and a maximal depth of 60 Å. The NA tetramers are composed of crystallographically equivalent monomers related by circular 4-fold symmetry. Each monomer folds into six antiparallel β-sheets of four strands. The secondary structure composition is 500% β-sheet. The remaining 50% of the residues form 24 strand connecting loops or turns. One of the loops contains a small α-helix. The structure of the complex of NA with DANA, a transition state analog, has enabled us to identify and characterize the site of enzyme catalysis. The center of mass of bound inhibitor is 32 Å from the 4-fold axis of the tetramer, lodged at the end of a shallow crater of diameter 16 Å with a depth of 8 to 10 Å. There are 12 amino acid residues that directly bind DANA, with a further six conserved amino acids lining the active site pocket. The neuraminidase inhibitor complex provides a three-dimensional model which will be used to further the understanding of enzymatic hydrolysis and aid the design of specific, anti-neuraminidase antiviral compounds.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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