Mannose-Binding Geometry of Pradimicin A
Mannose-Binding Geometry of Pradimicin A
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DOI：
10.1002/chem.201301368
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发表时间：
2013-08-05
影响因子：
4.3
通讯作者：
Ito, Yukishige
中科院分区：
文献类型：
--
作者：
Nakagawa, Yu;Doi, Takashi;Ito, Yukishige
Pradimicins（PRM）和benanomicins是唯一具有凝集素样性质的非肽类天然产物家族，即它们在Ca 2+离子存在下识别D-吡喃甘露糖苷（Man）。结合其独特的Man结合能力，它们通过与病原体的含Man聚糖结合而表现出抗真菌和抗HIV活性。尽管PRM作为凝集素模拟物和治疗先导物的巨大潜力，但它们识别Man的分子基础尚未建立。它们的聚集体形成倾向阻碍了溶液中的常规相互作用分析，并且PRM中两个Man结合位点的存在加剧了分析难度。在这项工作中，我们通过最近开发的分析策略，使用由1：1 PRM-A和Man的复合物。通过固态NMR光谱法对分子间距离的评估揭示Man的C2-C4区域与PRM-A的主要结合位点紧密接触，而Man的C1和C6位置相对较远。通过使用脱氧Man衍生物的共沉淀实验进一步验证了结合几何结构，从而提出PRM-A不仅与聚糖的非还原端的末端Man残基结合，而且与内部6-取代的Man残基结合。本研究为PRM-A的Man识别和聚糖特异性的分子基础提供了新的见解。
Pradimicins (PRMs) and benanomicins are the only family of nonpeptidic natural products with lectinlike properties, that is, they recognize D-mannopyranoside (Man) in the presence of Ca2+ ions. Coupled with their unique Man binding ability, they exhibit antifungal and anti-HIV activities through binding to Man-containing glycans of pathogens. Notwithstanding the great potential of PRMs as the lectin mimics and therapeutic leads, their molecular basis of Man recognition has yet to be established. Their aggregate-forming propensity has impeded conventional interaction analysis in solution, and the analytical difficulty is exacerbated by the existence of two Man binding sites in PRMs. In this work, we investigated the geometry of the primary Man binding of PRM-A, an original member of PRMs, by the recently developed analytical strategy using the solid aggregate composed of the 1: 1 complex of PRM-A and Man. Evaluation of intermolecular distances by solid-state NMR spectroscopy revealed that the C2-C4 region of Man is in close contact with the primary binding site of PRM-A, while the C1 and C6 positions of Man are relatively distant. The binding geometry was further validated by co-precipitation experiments using deoxy-Man derivatives, leading to the proposal that PRM-A binds not only to terminal Man residues at the non-reducing end of glycans, but also to internal 6-substituted Man residues. The present study provides new insights into the molecular basis of Man recognition and glycan specificity of PRM-A.