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首页> 外文期刊>Journal of Molecular Biology >Site-specific Discrimination by Cyanovirin-N for alpha-Linked Trisaccharides Comprising the Three Arms of Man(8) and Man(9).
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Site-specific Discrimination by Cyanovirin-N for alpha-Linked Trisaccharides Comprising the Three Arms of Man(8) and Man(9).

机译：Cyanovirin-N对包含Man（8）和Man（9）三臂的α-连接的三糖的位点特异性识别。

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Cyanovirin-N (CVN) is a novel cyanobacterial protein that selectively binds with nanomolar affinities the mammalian oligosaccharides Man(8) and Man(9). Consequently, CVN potently blocks HIV entry through highly avid carbohydrate-mediated interactions with the HIV-envelope glycoprotein gp120, and is under preclinical investigation as an anti-HIV microbicide. CVN contains two non-overlapping carbohydrate-binding sites that bind the disaccharide Manalpha(1-2)Manalpha (which represents the terminal disaccharide of all three arms of Man(9)) with low to sub-micromolar affinities. The solution structure of a 1:2 CVN:Manalpha(1-2)Manalpha complex revealed that CVN recognizes the stacked conformation of Manalpha(1-2)Manalpha through a deep hydrophilic-binding pocket on one side of the protein (site 2) and a semi-circular cleft on the other (site 1). With the prominent exception of the C1 hydroxyl group of the reducing mannopyranose ring, the bound disaccharide is positioned so that each hydroxyl group is involved in a direct or water-mediated hydrogen bond to the polar or charged side-chains comprising the binding pocket. Thus, to determine whether the next-most reducing mannopyranose ring will augment CVN affinity and selectivity, we have characterized by NMR and ITC the binding of CVN to three synthetic trisaccharides representing the full-length D1, D2 and D3 arms of mammalian oligomannosides. Our findings demonstrate that site 1 is able to discriminate between the three related trisaccharides methyl Manalpha(1-2)Manalpha(1-2)Man, methyl Manalpha(1-2)Manalpha(1-3)Man and methyl Manalpha(1-2)Manalpha(1-6)Man with remarkable selectivity, and binds these trisaccharides with K(A) values ranging from 8.1x10(3)M(-1) to 6.6x10(6)M(-1). Site 2 is less selective in that it binds all three trisaccharides with similar K(A) values ranging from 1.7 to 3.7(+/-0.3)x10(5)M(-1), but overall binds these trimannosides with higher affinities than site 1. The diversity of pathogenic organisms that display alpha(1-2)-linked mannosides on their cell surfaces suggests a broad defensive role for CVN in its cyanobacterial source.
机译：Cyanovirin-N（CVN）是一种新型的蓝细菌蛋白，可选择性地与纳摩尔浓度的哺乳动物寡糖Man（8）和Man（9）结合。因此，CVN通过高度狂热的碳水化合物介导的与HIV包膜糖蛋白gp120的相互作用，有效地阻止了HIV的进入，并且正在作为抗HIV杀微生物剂进行临床前研究。 CVN包含两个不重叠的碳水化合物结合位点，这些结合位点以低至亚微摩尔亲和力结合二糖Manalpha（1-2）Manalpha（代表Man（9）所有三个臂的末端二糖）。 1：2 CVN：Manalpha（1-2）Manalpha配合物的溶液结构表明，CVN通过蛋白质一侧的深亲水结合口袋（位点2）识别Manalpha（1-2）Manalpha的堆叠构象。另一个则是半圆形裂口（位置1）。除了还原甘露吡喃糖环的C1羟基以外，结合的二糖的位置应确保每个羟基都直接或直接通过水介导的氢键键合至构成结合袋的极性或带电侧链。因此，为了确定还原度最低的甘露吡喃糖环是否会增强CVN亲和力和选择性，我们已通过NMR和ITC表征了CVN与代表哺乳动物寡甘露糖苷的全长D1，D2和D3臂的三种合成三糖的结合。我们的发现表明位点1能够区分三种相关的三糖，即甲基Manalpha（1-2）Manalpha（1-2）Man，甲基Manalpha（1-2）Manalpha（1-3）Man和甲基Manalpha（1- 2）Manalpha（1-6）Man具有显着的选择性，并将这些三糖与K（A）值范围从8.1x10（3）M（-1）到6.6x10（6）M（-1）结合。位点2的选择性较低，因为它以1.7至3.7（+/- 0.3）x10（5）M（-1）的相似K（A）值结合所有三个三糖，但总体上以比位点更高的亲和力结合这些三甘露糖苷1.在其细胞表面显示与alpha（1-2）连接的甘露糖苷的病原生物的多样性表明，CVN在其蓝细菌来源中具有广泛的防御作用。

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