Structural Basis for the Binding Mechanism of Human Serum Albumin Complexed with Cyclic Peptide Dalbavancin
Structural Basis for the Binding Mechanism of Human Serum Albumin Complexed with Cyclic Peptide Dalbavancin
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DOI：
10.1021/acs.jmedchem.0c01578
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发表时间：
2020-11-25
影响因子：
7.3
通讯作者：
Wakui, Naoki
中科院分区：
文献类型：
--
作者：
Ito, Sho;Senoo, Akinobu;Wakui, Naoki
具有独特结构特征的环肽已成为药物发现的新候选者;它们与人血清白蛋白（HSA;长血液半衰期）的关联对于改善药物递送和避免肾清除至关重要。在这里，我们提出的晶体结构的HSA复合达巴霉素，临床上使用的环肽。小角X射线散射和等温滴定量热实验表明，HSA-达巴万星复合物以单体状态存在;在溶液中，达巴万星仅与HSA的亚结构域IA结合。结构分析和分子动力学模拟表明，Phe 70的摆动和附近的达巴万星的螺旋运动是必要的结合。Leu 251的翻转促进了具有诱导拟合机制的结合口袋的形成;此外，包括Glu 60的环区域的移动增加了与HSA的非共价相互作用的数量。这些发现可能支持开发新的环肽用于临床，特别是阐明其与HSA的结合机制。
Cyclic peptides, with unique structural features, have emerged as new candidates for drug discovery; their association with human serum albumin (HSA; long blood half-life) is crucial to improve drug delivery and avoid renal clearance. Here, we present the crystal structure of HSA complexed with dalbavancin, a clinically used cyclic peptide. Small-angle X-ray scattering and isothermal titration calorimetry experiments showed that the HSA-dalbavancin complex exists in a monomeric state; dalbavancin is only bound to the subdomain IA of HSA in solution. Structural analysis and MD simulation revealed that the swing of Phe70 and movement of the helix near dalbavancin were necessary for binding. The flip of Leu251 promoted the formation of the binding pocket with an induced-fit mechanism; moreover, the movement of the loop region including Glu60 increased the number of noncovalent interactions with HSA. These findings may support the development of new cyclic peptides for clinical use, particularly the elucidation of their binding mechanism to HSA.