The α1-acid glycoprotein (AGP) is an abundant blood plasma protein with important immunomodulatory functions coupled to endogenous and exogenous ligand-binding properties. Its affinity for many drug-like structures, however, means AGP can have a significant effect on the pharmokinetics and pharmacodynamics of numerous small molecule therapeutics. Staurosporine, and its hydroxylated forms UCN-01 and UCN-02, are kinase inhibitors that have been investigated at length as antitumour compounds. Despite their potency, these compounds display poor pharmokinetics due to binding to both AGP variants, AGP1 and AGP2. The recent renewed interest in UCN-01 as a cytostatic protective agent prompted us to solve the structure of the AGP2-UCN-01 complex by X-ray crystallography, revealing for the first time the precise binding mode of UCN-01. The solution NMR suggests AGP2 undergoes a significant conformational change upon ligand binding, but also that it uses a common set of sidechains with which it captures key groups of UCN-01 and other small molecule ligands. We anticipate that this structure and the supporting NMR data will facilitate rational redesign of small molecules that could evade AGP and therefore improve tissue distribution.

中文翻译：

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α1-酸性糖蛋白与强效抗肿瘤化合物 UCN-01 高亲和力结合的结构基础。

α1-酸性糖蛋白 (AGP) 是一种丰富的血浆蛋白，具有与内源性和外源性配体结合特性相结合的重要免疫调节功能。然而，它对许多药物样结构的亲和力意味着 AGP 可以对许多小分子疗法的药代动力学和药效学产生显着影响。星形孢菌素及其羟基化形式 UCN-01 和 UCN-02 是激酶抑制剂，已作为抗肿瘤化合物进行了深入研究。尽管它们具有效力，但由于与 AGP 变体 AGP1 和 AGP2 结合，这些化合物显示出较差的药代动力学。最近对 UCN-01 作为细胞抑制保护剂的重新兴趣促使我们通过 X 射线晶体学解决 AGP2-UCN-01 复合物的结构，首次揭示了 UCN-01 的精确结合模式。解决方案 NMR 表明 AGP2 在配体结合时经历了显着的构象变化，但它也使用一组常见的侧链来捕获 UCN-01 和其他小分子配体的关键基团。我们预计这种结构和支持的 NMR 数据将有助于合理重新设计可以逃避 AGP 并因此改善组织分布的小分子。