Monomerization of the viral entry inhibitor griffithsin yields insights into the relationship between multivalent binding to high mannose oligosaccharides and antiviral activity
Identifieur interne : 001464 ( Main/Exploration ); précédent : 001463; suivant : 001465Monomerization of the viral entry inhibitor griffithsin yields insights into the relationship between multivalent binding to high mannose oligosaccharides and antiviral activity
Auteurs : Tinoush Moulaei [États-Unis] ; Shilpa R. Shenoy [États-Unis] ; Barbara Giomarelli [États-Unis] ; Cheryl Thomas [États-Unis] ; James B. Mcmahon [États-Unis] ; Zbigniew Dauter [États-Unis] ; Barry R. O Eefe [États-Unis] ; Alexander Wlodawer [États-Unis]Source :
- Structure(London, England:1993) [ 0969-2126 ] ; 2010.
Abstract
Mutations were introduced to the domain-swapped homodimer of the antiviral lectin griffithsin (GRFT). Whereas several single and double mutants remained dimeric, insertion of either two or four amino acids at the dimerization interface resulted in a monomeric form of the protein (mGRFT). Monomeric character of the modified proteins was confirmed by sedimentation equilibrium ultracentrifugation and by their high resolution X-ray crystal structures, whereas their binding to carbohydrates was assessed by isothermal titration calorimetry. Cell-based antiviral activity assays utilizing different variants of mGRFT indicated that the monomeric form of the lectin had greatly reduced activity against HIV-1, suggesting that the antiviral activity of GRFT stems from crosslinking and aggregation of viral particles via multivalent interactions between GRFT and oligosaccharides present on HIV envelope glycoproteins. Atomic resolution crystal structure of a complex between mGRFT and nonamannoside revealed that a single mGRFT molecule binds to two different nonamannoside molecules through all three carbohydrate-binding sites present on the monomer.
Url:
DOI: 10.1016/j.str.2010.05.016
PubMed: 20826337
PubMed Central: 3399781
Affiliations:
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Mcmahon</name><affiliation wicri:level="2"><nlm:aff id="A2">Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702-1201, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702-1201</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Dauter, Zbigniew" sort="Dauter, Zbigniew" uniqKey="Dauter Z" first="Zbigniew" last="Dauter">Zbigniew Dauter</name><affiliation wicri:level="2"><nlm:aff id="A4">Synchrotron Radiation Research Section, Macromolecular Crystallography Laboratory, National Cancer Institute, Argonne National Laboratory, Argonne, IL 60439, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Synchrotron Radiation Research Section, Macromolecular Crystallography Laboratory, National Cancer Institute, Argonne National Laboratory, Argonne, IL 60439</wicri:regionArea><placeName><region type="state">Illinois</region></placeName></affiliation></author><author><name sortKey="O Eefe, Barry R" sort="O Eefe, Barry R" uniqKey="O Eefe B" first="Barry R." last="O Eefe">Barry R. O Eefe</name><affiliation wicri:level="2"><nlm:aff id="A2">Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702-1201, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702-1201</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Wlodawer, Alexander" sort="Wlodawer, Alexander" uniqKey="Wlodawer A" first="Alexander" last="Wlodawer">Alexander Wlodawer</name><affiliation wicri:level="2"><nlm:aff id="A1">Protein Structure Section, Macromolecular Crystallography Laboratory, National Cancer, Institute-Frederick, Frederick, MD 21702-1201, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Protein Structure Section, Macromolecular Crystallography Laboratory, National Cancer, Institute-Frederick, Frederick, MD 21702-1201</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author></analytic><series><title level="j">Structure(London, England:1993)</title><idno type="ISSN">0969-2126</idno><idno type="eISSN">1878-4186</idno><imprint><date when="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>SUMMARY</title><p id="P1">Mutations were introduced to the domain-swapped homodimer of the antiviral lectin griffithsin (GRFT). Whereas several single and double mutants remained dimeric, insertion of either two or four amino acids at the dimerization interface resulted in a monomeric form of the protein (mGRFT). Monomeric character of the modified proteins was confirmed by sedimentation equilibrium ultracentrifugation and by their high resolution X-ray crystal structures, whereas their binding to carbohydrates was assessed by isothermal titration calorimetry. Cell-based antiviral activity assays utilizing different variants of mGRFT indicated that the monomeric form of the lectin had greatly reduced activity against HIV-1, suggesting that the antiviral activity of GRFT stems from crosslinking and aggregation of viral particles via multivalent interactions between GRFT and oligosaccharides present on HIV envelope glycoproteins. Atomic resolution crystal structure of a complex between mGRFT and nonamannoside revealed that a single mGRFT molecule binds to two different nonamannoside molecules through all three carbohydrate-binding sites present on the monomer.</p></div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Illinois</li><li>Maryland</li></region></list><tree><country name="États-Unis"><region name="Maryland"><name sortKey="Moulaei, Tinoush" sort="Moulaei, Tinoush" uniqKey="Moulaei T" first="Tinoush" last="Moulaei">Tinoush Moulaei</name></region><name sortKey="Dauter, Zbigniew" sort="Dauter, Zbigniew" uniqKey="Dauter Z" first="Zbigniew" last="Dauter">Zbigniew Dauter</name><name sortKey="Giomarelli, Barbara" sort="Giomarelli, Barbara" uniqKey="Giomarelli B" first="Barbara" last="Giomarelli">Barbara Giomarelli</name><name sortKey="Mcmahon, James B" sort="Mcmahon, James B" uniqKey="Mcmahon J" first="James B." last="Mcmahon">James B. Mcmahon</name><name sortKey="O Eefe, Barry R" sort="O Eefe, Barry R" uniqKey="O Eefe B" first="Barry R." last="O Eefe">Barry R. O Eefe</name><name sortKey="Shenoy, Shilpa R" sort="Shenoy, Shilpa R" uniqKey="Shenoy S" first="Shilpa R." last="Shenoy">Shilpa R. Shenoy</name><name sortKey="Shenoy, Shilpa R" sort="Shenoy, Shilpa R" uniqKey="Shenoy S" first="Shilpa R." last="Shenoy">Shilpa R. Shenoy</name><name sortKey="Thomas, Cheryl" sort="Thomas, Cheryl" uniqKey="Thomas C" first="Cheryl" last="Thomas">Cheryl Thomas</name><name sortKey="Wlodawer, Alexander" sort="Wlodawer, Alexander" uniqKey="Wlodawer A" first="Alexander" last="Wlodawer">Alexander Wlodawer</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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