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Orientation of sugars bound to the principal C-type carbohydrate-recognition domain of the macrophage mannose receptor.

机译:与巨噬细胞甘露糖受体的主要C型碳水化合物识别域结合的糖的取向。

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摘要

The extracellular region of the macrophage mannose receptor, a protein involved in the innate immune response, contains eight C-type carbohydrate-recognition domains (CRDs). The fourth of these domains, CRD-4, is central to ligand binding by the receptor, and binds mannose, fucose and N-acetylglucosamine by direct ligation to Ca2+. Site-directed mutagenesis combined with NMR and molecular modelling have been used to determine the orientation of monosaccharides bound to CRD-4. Two resonances in the 1H NMR spectrum of CRD-4 that are perturbed on sugar binding are identified as a methyl proton from a leucine side chain in the core of the domain and the H-2 proton of a histidine close to the predicted sugar-binding site. The effects of mutagenesis of this histidine residue, a nearby isoleucine residue and a tyrosine residue previously shown to stack against sugars bound to CRD-4 show the absolute orientation of sugars in the binding site. N-Acetylglucosamine binds to CRD-4 of the mannose receptor in the orientation seen in crystal structures of the CRD of rat liver mannose-binding protein. Mannose binds to CRD-4 in the orientation seen in the CRD of rat serum mannose-binding protein and is rotated by 180 degrees relative to GlcNAc bound to CRD-4. Interaction of the O-methyl group and C-1 of alpha-methyl Fuc with the tyrosine residue accounts for the strong preference of CRD-4 for this anomer of fucose. Both anomers of fucose bind to CRD-4 in the orientation seen in rat liver mannose-binding protein.
机译:巨噬细胞甘露糖受体的一种胞外区域,一种参与先天免疫应答的蛋白质,包含八个C型碳水化合物识别域(CRD)。这些结构域中的第四个域CRD-4是受体与配体结合的关键,并通过直接连接至Ca2 +与甘露糖,岩藻糖和N-乙酰氨基葡萄糖结合。结合NMR和分子模型的定点诱变已用于确定与CRD-4结合的单糖的方向。 CRD-4的1H NMR光谱中两个受糖结合干扰的共振被确定为来自域核心亮氨酸侧链的甲基质子和接近预测糖结合的组氨酸的H-2质子现场。该组氨酸残基,附近的异亮氨酸残基和酪氨酸残基的诱变作用先前显示出可与结合CRD-4的糖堆叠,显示出糖在结合位点的绝对方向。 N-乙酰氨基葡萄糖以大鼠肝甘露糖结合蛋白CRD晶体结构中所见的方向与甘露糖受体的CRD-4结合。甘露糖以在大鼠血清甘露糖结合蛋白的CRD中看到的方向与CRD-4结合,并且相对于与CRD-4结合的GlcNAc旋转180度。 O-甲基和α-甲基Fuc的C-1与酪氨酸残基的相互作用说明了CRD-4对于岩藻糖的这种异构体的强烈偏好。岩藻糖的两个端基异构体均以大鼠肝脏甘露糖结合蛋白中所见的方向与CRD-4结合。

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