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• W1839399288 abstract "The protein DC-SIGNR (Dendritic-cell specific ICAM3 grabbing non-integrinrelated) is a C-type (calcium-dependent) lectin, which binds highly-branchedmannose oligosaccharides. DC-SIGNR interacts with a range of deadly diseases viasurface glycans on pathogenic glycoproteins, and the ability of DC-SIGNR toincrease the rate of infection of viruses including human immunodeficiency virus(HIV) and hepatitis C virus (HCV) makes the study of DC-SIGNR/oligosaccharideinteractions very attractive. The research described in this thesis sought to gaininsight into the calcium and ligand binding properties of the DC-SIGNRcarbohydrate recognition domain (CRD) in solution by utilising solution statenuclear magnetic resonance spectroscopy (NMR).A protocol for the production of uniformly 15N /13C labelled DC-SIGNR CRDwas developed, allowing the acquisition of heteronuclear NMR experiments andthe first assignment of the calcium-bound (holo) DC-SIGNR CRD to be reported.The assignment has allowed investigation of calcium and glycan binding, as wellas the pH dependence of the DC-SIGNR CRD.The data presented in this thesis reveal that the DC-SIGNR CRD is highlydynamic in the calcium-free state, with the addition of calcium resulting in globalconformational and dynamic changes throughout the CRD. While calcium bindinghinders the protein dynamics (particularly in the calcium binding regions), a largedegree of mobility remains. The evidence that ligands are released at low pHsuggests that DC-SIGNR may act as an endocytic receptor.In addition to calcium binding, interactions of the DC-SIGNR CRD with arange of ligands were investigated. In particular, interactions with theoligosaccharide Man9GlcNAc (present on the HIV viral envelope) are described,representing the first direct study of the CRD interacting with a diseaseassociatedligand. The glycans employed in this study all bind to the primarycalcium binding site, supporting previous crystal data. However, each glycandisplays distinct patterns of chemical shift perturbations implying that they eachhave different, extended binding modes. Particularly striking is the differencebetween the disease-associated Man9GlcNAc ligand and the ligand present in apreviously published crystal structure, (GlcNAc)2Man3.An investigation of the dynamics of the CRD in the holo form and boundto the ligand Man5 shows that the CRD is highly dynamic and that glycan bindingfurther hinders, but does not abolish, the molecular motions. The dynamics dataalso suggests that a ligand-induced conformational change may occur andindicates potential new binding sites which are not present in any publishedcrystal structures. The dynamic nature of the DC-SIGNR CRD may explain the widerange of ligand specificities and affinities of the C-type lectin scaffold andsuggests that the study of the ligand binding properties and dynamics of proteinssuch as DC-SIGNR in solution is essential to further understanding of this class ofproteins." @default.
• W1839399288 created "2016-06-24" @default.
• W1839399288 creator A5064381936 @default.
• W1839399288 date "2012-12-01" @default.
• W1839399288 modified "2023-09-27" @default.
• W1839399288 title "A solution state NMR study of the structure and ligand binding properties of the human C-type lectin DC-SIGNR" @default.
• W1839399288 hasPublicationYear "2012" @default.
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