Solution NMR analyses of the C-type carbohydrate recognition domain of DC-SIGNR protein reveal different binding modes for HIV-derived oligosaccharides and smaller glycan fragments.
Identifieur interne : 001858 ( Main/Exploration ); précédent : 001857; suivant : 001859Solution NMR analyses of the C-type carbohydrate recognition domain of DC-SIGNR protein reveal different binding modes for HIV-derived oligosaccharides and smaller glycan fragments.
Auteurs : Fay Probert [Royaume-Uni] ; Sara B-M Whittaker ; Max Crispin ; Daniel A. Mitchell ; Ann M. DixonSource :
- The Journal of biological chemistry [ 1083-351X ] ; 2013.
Descripteurs français
- KwdFr :
- Lectines de type C (), Lectines de type C (métabolisme), Liaison aux protéines, Modèles moléculaires, Molécules d'adhérence cellulaire (), Molécules d'adhérence cellulaire (métabolisme), Oligosaccharides (), Oligosaccharides (métabolisme), Polyosides (), Polyosides (métabolisme), Récepteurs de surface cellulaire (), Récepteurs de surface cellulaire (métabolisme), Résonance magnétique nucléaire biomoléculaire (), VIH (Virus de l'Immunodéficience Humaine) ().
- MESH :
- métabolisme : Lectines de type C, Molécules d'adhérence cellulaire, Oligosaccharides, Polyosides, Récepteurs de surface cellulaire.
- Lectines de type C, Liaison aux protéines, Modèles moléculaires, Molécules d'adhérence cellulaire, Oligosaccharides, Polyosides, Récepteurs de surface cellulaire, Résonance magnétique nucléaire biomoléculaire, VIH (Virus de l'Immunodéficience Humaine).
English descriptors
- KwdEn :
- Cell Adhesion Molecules (chemistry), Cell Adhesion Molecules (metabolism), HIV (chemistry), Lectins, C-Type (chemistry), Lectins, C-Type (metabolism), Models, Molecular, Nuclear Magnetic Resonance, Biomolecular (methods), Oligosaccharides (chemistry), Oligosaccharides (metabolism), Polysaccharides (chemistry), Polysaccharides (metabolism), Protein Binding, Receptors, Cell Surface (chemistry), Receptors, Cell Surface (metabolism).
- MESH :
- chemical , chemistry : Cell Adhesion Molecules, Lectins, C-Type, Oligosaccharides, Polysaccharides, Receptors, Cell Surface.
- chemical , metabolism : Cell Adhesion Molecules, Lectins, C-Type, Oligosaccharides, Polysaccharides, Receptors, Cell Surface.
- chemistry : HIV.
- methods : Nuclear Magnetic Resonance, Biomolecular.
- Models, Molecular, Protein Binding.
Abstract
The C-type lectin DC-SIGNR (dendritic cell-specific ICAM-3-grabbing non-integrin-related; also known as L-SIGN or CD299) is a promising drug target due to its ability to promote infection and/or within-host survival of several dangerous pathogens (e.g. HIV and severe acute respiratory syndrome coronavirus (SARS)) via interactions with their surface glycans. Crystallography has provided excellent insight into the mechanism by which DC-SIGNR interacts with small glycans, such as (GlcNAc)2Man3; however, direct observation of complexes with larger, physiological oligosaccharides, such as Man9GlcNAc2, remains elusive. We have utilized solution-state nuclear magnetic resonance spectroscopy to investigate DC-SIGNR binding and herein report the first backbone assignment of its active, calcium-bound carbohydrate recognition domain. Direct interactions with the small sugar fragments Man3, Man5, and (GlcNAc)2Man3 were investigated alongside Man9GlcNAc derived from recombinant gp120 (present on the HIV viral envelope), providing the first structural data for DC-SIGNR in complex with a virus-associated ligand, and unique binding modes were observed for each glycan. In particular, our data show that DC-SIGNR has a different binding mode for glycans on the HIV viral envelope compared with the smaller glycans previously observed in the crystalline state. This suggests that using the binding mode of Man9GlcNAc, instead of those of small glycans, may provide a platform for the design of DC-SIGNR inhibitors selective for high mannose glycans (like those on HIV). (15)N relaxation measurements provided the first information on the dynamics of the carbohydrate recognition domain, demonstrating that it is a highly flexible domain that undergoes ligand-induced conformational and dynamic changes that may explain the ability of DC-SIGNR to accommodate a range of glycans on viral surfaces.
DOI: 10.1074/jbc.M113.458299
PubMed: 23788638
Affiliations:
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Le document en format XML
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Mitchell</name></author><author><name sortKey="Dixon, Ann M" sort="Dixon, Ann M" uniqKey="Dixon A" first="Ann M" last="Dixon">Ann M. Dixon</name></author></analytic><series><title level="j">The Journal of biological chemistry</title><idno type="eISSN">1083-351X</idno><imprint><date when="2013" type="published">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Cell Adhesion Molecules (chemistry)</term><term>Cell Adhesion Molecules (metabolism)</term><term>HIV (chemistry)</term><term>Lectins, C-Type (chemistry)</term><term>Lectins, C-Type (metabolism)</term><term>Models, Molecular</term><term>Nuclear Magnetic Resonance, Biomolecular (methods)</term><term>Oligosaccharides (chemistry)</term><term>Oligosaccharides (metabolism)</term><term>Polysaccharides (chemistry)</term><term>Polysaccharides (metabolism)</term><term>Protein Binding</term><term>Receptors, Cell Surface (chemistry)</term><term>Receptors, Cell Surface (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Lectines de type C ()</term><term>Lectines de type C (métabolisme)</term><term>Liaison aux protéines</term><term>Modèles moléculaires</term><term>Molécules d'adhérence cellulaire ()</term><term>Molécules d'adhérence cellulaire (métabolisme)</term><term>Oligosaccharides ()</term><term>Oligosaccharides (métabolisme)</term><term>Polyosides ()</term><term>Polyosides (métabolisme)</term><term>Récepteurs de surface cellulaire ()</term><term>Récepteurs de surface cellulaire (métabolisme)</term><term>Résonance magnétique nucléaire biomoléculaire ()</term><term>VIH (Virus de l'Immunodéficience Humaine) ()</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Cell Adhesion Molecules</term><term>Lectins, C-Type</term><term>Oligosaccharides</term><term>Polysaccharides</term><term>Receptors, Cell Surface</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Cell Adhesion Molecules</term><term>Lectins, C-Type</term><term>Oligosaccharides</term><term>Polysaccharides</term><term>Receptors, Cell Surface</term></keywords><keywords scheme="MESH" qualifier="chemistry" xml:lang="en"><term>HIV</term></keywords><keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Nuclear Magnetic Resonance, Biomolecular</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Lectines de type C</term><term>Molécules d'adhérence cellulaire</term><term>Oligosaccharides</term><term>Polyosides</term><term>Récepteurs de surface cellulaire</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Models, Molecular</term><term>Protein Binding</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Lectines de type C</term><term>Liaison aux protéines</term><term>Modèles moléculaires</term><term>Molécules d'adhérence cellulaire</term><term>Oligosaccharides</term><term>Polyosides</term><term>Récepteurs de surface cellulaire</term><term>Résonance magnétique nucléaire biomoléculaire</term><term>VIH (Virus de l'Immunodéficience Humaine)</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The C-type lectin DC-SIGNR (dendritic cell-specific ICAM-3-grabbing non-integrin-related; also known as L-SIGN or CD299) is a promising drug target due to its ability to promote infection and/or within-host survival of several dangerous pathogens (e.g. HIV and severe acute respiratory syndrome coronavirus (SARS)) via interactions with their surface glycans. Crystallography has provided excellent insight into the mechanism by which DC-SIGNR interacts with small glycans, such as (GlcNAc)2Man3; however, direct observation of complexes with larger, physiological oligosaccharides, such as Man9GlcNAc2, remains elusive. We have utilized solution-state nuclear magnetic resonance spectroscopy to investigate DC-SIGNR binding and herein report the first backbone assignment of its active, calcium-bound carbohydrate recognition domain. Direct interactions with the small sugar fragments Man3, Man5, and (GlcNAc)2Man3 were investigated alongside Man9GlcNAc derived from recombinant gp120 (present on the HIV viral envelope), providing the first structural data for DC-SIGNR in complex with a virus-associated ligand, and unique binding modes were observed for each glycan. In particular, our data show that DC-SIGNR has a different binding mode for glycans on the HIV viral envelope compared with the smaller glycans previously observed in the crystalline state. This suggests that using the binding mode of Man9GlcNAc, instead of those of small glycans, may provide a platform for the design of DC-SIGNR inhibitors selective for high mannose glycans (like those on HIV). (15)N relaxation measurements provided the first information on the dynamics of the carbohydrate recognition domain, demonstrating that it is a highly flexible domain that undergoes ligand-induced conformational and dynamic changes that may explain the ability of DC-SIGNR to accommodate a range of glycans on viral surfaces. </div></front></TEI><affiliations><list><country><li>Royaume-Uni</li></country></list><tree><noCountry><name sortKey="Crispin, Max" sort="Crispin, Max" uniqKey="Crispin M" first="Max" last="Crispin">Max Crispin</name><name sortKey="Dixon, Ann M" sort="Dixon, Ann M" uniqKey="Dixon A" first="Ann M" last="Dixon">Ann M. Dixon</name><name sortKey="Mitchell, Daniel A" sort="Mitchell, Daniel A" uniqKey="Mitchell D" first="Daniel A" last="Mitchell">Daniel A. Mitchell</name><name sortKey="Whittaker, Sara B M" sort="Whittaker, Sara B M" uniqKey="Whittaker S" first="Sara B-M" last="Whittaker">Sara B-M Whittaker</name></noCountry><country name="Royaume-Uni"><noRegion><name sortKey="Probert, Fay" sort="Probert, Fay" uniqKey="Probert F" first="Fay" last="Probert">Fay Probert</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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