Crystal structures of human transthyretin complexed with glabridin.
Crystal structures of human transthyretin complexed with glabridin.
复制标题
人转甲状腺素蛋白与光甘草定复合物的晶体结构。
DOI：
10.1021/jm401832j
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Mizuguchi M.
中科院分区：
文献类型：
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作者：
Yokoyama T;Kosaka Y;Mizuguchi M.
转甲状腺素(TTR)是一种与人类淀粉样变性疾病有关的血浆蛋白。几个小分子结合到TTR四聚体的甲状腺激素结合部位，可以稳定TTR四聚体，抑制TTR四聚体淀粉样纤维的形成。在此，我们在硫代黄素实验中证明了光面甘草异黄素(GLab)，一种从光面甘草中分离出来的异黄酮烯基化产物，能抑制TTR的聚集。TtR-GLaB复合体结构揭示了一种新的结合模式，包括CH−π与A108的相互作用和与K15的氢键。与野生型apo结构的结构比较表明，CH−π与A108的相互作用因GLab结合时的诱导Fit构象变化而增强。此外，GLab的结合诱导了T119侧链的旋转和水分子的加入，导致了二聚体-二聚体界面的稳定。这些结果表明，GLab是一种新的TTR纤化抑制剂，并提示了GLab结合稳定四聚体的分子机制。
Transthyretin (TTR) is a plasma protein implicated in human amyloid diseases. Several small molecules that bind to the thyroxine-binding site of TTR have been shown to stabilize the TTR tetramer and to inhibit amyloid fibril formation of TTR. Herein, we demonstrated that glabridin (Glab), a prenylated isoflavan isolated from Glycyrrhiza glabra L., inhibited aggregation of TTR in a thioflavin assay. The TTR–Glab complex structure revealed a novel binding mode including a CH−π interaction with A108 and a hydrogen bond with K15. A structural comparison with the wild type-apo structure revealed that the CH−π interaction with A108 was strengthened by the induced-fit conformational change upon Glab binding. Furthermore, the binding of Glab induced a rotation of the T119 side chain, and the inclusion of a water molecule, leading to stabilization of the dimer–dimer interface. These results demonstrate that Glab is a novel inhibitor of TTR fibrillization and suggest the molecular mechanism by which Glab binding stabilizes the tetramer.