Oligosaccharide substrate interactions with beta-1,4-Gal

寡糖底物与 β-1,4-Gal 的相互作用

基本信息

项目摘要

The oligosaccharide moieties of glycoconjugates play important roles in several biological processes of a cell, including the folding and transport of glycoproteins across cellular compartments. For the biosynthesis of these complex oligosaccharides intricate machineries exists in a cell. Defective glycan synthesis has serious pathological consequences and results in several human diseases. The oligosaccharide moieties bind to cellular proteins with high specificity and modulate the homo- and hetro-dimerization of glycoproteins. Due to the conformational flexibility of oligosaccharides, the torsional angles of a disaccharide unit, especially around the1-6-linkage, adjust in such a way that the side groups of the oligosaccharides orient themselves in a manner that promotes favorable interactions with the binding residues of the protein. Branched oligosaccharides cross-link proteins and generate infinite networks of protein-carbohydrate complexes, resulting in the modulation of various cell responses. Although all beta-4Gal-T-family members, that are responsible for the synthesis of beta-linked Gal moieties in different oligosaccharides, transfer Gal to GlcNAc, each recognizes differently the remaining monosaccharide units of the oligosaccharide to which GlcNAc is attached. The sequence comparison of the human b4Gal-T family members and the structural homology models based on the 3D structure of b4Gal-T1 reveals only a little or no variation in the GlcNAc binding site among the family members, where as the extended oligosaccharide binding region shows significant variations. This indicates that these enzymes may prefer different GlcNAc containing oligosaccharides as their preferred sugar acceptors. To determine the exact mode of binding of the oligosaccharide in the binding site we have carried out the crystal structure analysis of the b4Gal-T1-oligosaccharide complexes, enzyme kinetic analysis and MD simulations. Defining the oligosaccharide binding site of b4Gal-T1 by crystal structure investigations of the complexes with the oligosaccharides : By molecular modeling and docking studies we have previously defined the oligosaccharide binding site of b4Gal-T1, the 3D-structure of which has been determined in our laboratory, either in complex with UDP-galactose and Mn2+ion, or in complex with alpha-lactalbumin and N-acetylglucosamine (see Project # Z01 BC 009304), or of the mutant Met344His-b4Gal-T1 in complex with chitobiose (see Project # Z01 BC 009305). Examination of the GlcNAc binding site in b4Gal-T1 from the crystal structure reveals an "open canal shaped" extended sugar binding site that lay behind the GlcNAc binding site. This site is formed by the residues from three regions; residues 280 to 289, residues 319 to 325 and residues 359 to 368. In the crystal structure of b4Gal-T1-LA-complex, LA binds to this region and therefore LA is expected to compete with the GlcNAc containing oligosaccharides, such as chitobiose. Crystallization of the wild type b4Gal-T1with the acceptor either in the presence or absence of UDP has not been successful. This is mainly due to the absence of the acceptor binding-site in the apo-b4Gal-T1 that exists in the open conformation. The enzyme has been crystallized in the closed conformation, where the acceptor site is present, only when UDP-Gal is bound. Although UDP or the acceptor molecules can induce the essential conformational changes, such complexes have been crystallized thus far only in the presence of LA. Since LA binds to the extended sugar binding site it is not possible to crystallize b4Gal-T1 with the oligosaccharide acceptors in the presence of LA.
糖缀合物的寡糖部分在细胞的几个生物过程中发挥重要作用,包括糖蛋白的折叠和跨细胞区室的运输。对于这些复杂的低聚糖的生物合成,细胞中存在着复杂的机制。糖合成缺陷具有严重的病理后果,并导致多种人类疾病。寡糖部分以高特异性结合细胞蛋白,并调节糖蛋白的同源和异二聚化。由于低聚糖的构象灵活性,双糖单元的扭转角度,特别是在1-6键周围,以这样一种方式调整,即低聚糖的侧基以一种促进与蛋白质结合残基有利相互作用的方式定位自己。支链低聚糖交联蛋白质并产生无限的蛋白质-碳水化合物网络,导致各种细胞反应的调节。

项目成果

期刊论文数量(0)
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Pradman K Qasba其他文献

Pradman K Qasba的其他文献

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{{ truncateString('Pradman K Qasba', 18)}}的其他基金

Oligosaccharide Interactions with Proteins
低聚糖与蛋白质的相互作用
  • 批准号:
    6559116
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Structural Studies and 3D Structure Determination of Recombinant <FONT FACE=symb
重组体的结构研究和 3D 结构测定 <FONT FACE=symb
  • 批准号:
    6433157
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Oligosaccharide substrate interactions with beta-1,4-Ga
寡糖底物与 beta-1,4-Ga 的相互作用
  • 批准号:
    6944635
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Detection of Specific Glycan Moieties on the Cell Surface
细胞表面特定聚糖部分的检测
  • 批准号:
    8349512
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Utilizing Glycosyltransferases for Bioconjugation
利用糖基转移酶进行生物共轭
  • 批准号:
    8552799
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Oligosaccharide Substrate and Inhibitor Interactions with beta-1,4-Gal-T1
寡糖底物和抑制剂与 β-1,4-Gal-T1 的相互作用
  • 批准号:
    7965207
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Oligosaccharide Substrate and Inhibitor Interactions with beta-1,4-Gal-T1
寡糖底物和抑制剂与 β-1,4-Gal-T1 的相互作用
  • 批准号:
    7732974
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Using Glycosyltransferases for Conjugation of Single-Chain Antibodies and Lipids
使用糖基转移酶缀合单链抗体和脂质
  • 批准号:
    8157471
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
PRINCIPALS OF CONFORMATIONAL ANALYSIS OF CARBOHYDRATES - A TEXT BOOK
碳水化合物构象分析原理 - 教科书
  • 批准号:
    6289310
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Structure-Function Studies and Design of Novel Glycosyltransferases
新型糖基转移酶的结构功能研究和设计
  • 批准号:
    7965164
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:

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Oligosaccharide Interactions with Proteins
低聚糖与蛋白质的相互作用
  • 批准号:
    6559116
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Oligosaccharide substrate interactions with beta-1,4-Ga
寡糖底物与 beta-1,4-Ga 的相互作用
  • 批准号:
    6944635
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Oligosaccharide Substrate and Inhibitor Interactions with beta-1,4-Gal-T1
寡糖底物和抑制剂与 β-1,4-Gal-T1 的相互作用
  • 批准号:
    7965207
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Oligosaccharide Substrate and Inhibitor Interactions with beta-1,4-Gal-T1
寡糖底物和抑制剂与 β-1,4-Gal-T1 的相互作用
  • 批准号:
    7732974
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  • 资助金额:
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OLIGOSACCHARIDE CONFORMATIONS AND THEIR INTERACTIONS WITH PROTEINS
低聚糖构象及其与蛋白质的相互作用
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    6101031
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Oligosaccharide Substrate and Inhibitor Interactions with beta-1,4-Gal-T1
寡糖底物和抑制剂与 β-1,4-Gal-T1 的相互作用
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Oligosaccharide Substrate and Inhibitor Interactions with beta-1,4-Gal-T1
寡糖底物和抑制剂与 β-1,4-Gal-T1 的相互作用
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OLIGOSACCHARIDE CONFORMATIONS AND THEIR INTERACTIONS WITH PROTEINS
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