Misfolding and aggregation of immunoglobulin light chains (LCs) leads to the degeneration of post-mitotic tissue in the disease immunoglobulin LC amyloidosis (AL). We previously reported the discovery of small molecule kinetic stabilizers of the native dimeric structure of full-length LCs, which slow or stop the LC aggregation cascade at the outset. A predominant structural category of kinetic stabilizers emerging from the high-throughput screen are coumarins substituted at the 7-position, which bind at the interface between the two variable domains of the light chain dimer. Here, we report the binding mode of another, more polar, LC kinetic stabilizer chemotype, 3,5-substituted hydantoins. Computational docking, solution nuclear magnetic resonance experiments, and x-ray crystallography show that the aromatic substructure emerging from the hydantoin 3-position occupies the same LC binding site as the coumarin ring. Notably, the hydantoin ring extends beyond the binding site mapped out by the coumarin hits. The hydantoin ring makes hydrogen bonds with both LC monomers simultaneously. The alkyl substructure at the hydantoin 5-position partially occupies a novel binding pocket proximal to the pocket occupied by the coumarin substructure. Overall, the hydantoin structural data suggest that a larger area of the LC variable-domain–variable-domain dimer interface is amenable to small molecule binding than previously demonstrated, which should facilitate development of more potent full-length LC kinetic stabilizers.

免疫球蛋白轻链 (LC) 的错误折叠和聚集导致疾病免疫球蛋白轻链淀粉样变性 (AL) 中的有丝分裂后组织退化。我们之前报道了全长 LC 的天然二聚体结构的小分子动力学稳定剂的发现，它们在一开始就减慢或停止了 LC 聚集级联。从高通量筛选中出现的动力学稳定剂的主要结构类别是在 7 位取代的香豆素，其结合在轻链二聚体的两个可变域之间的界面处。在这里，我们报告了另一种极性更强的 LC 动力学稳定剂化学型、3,5-取代乙内酰脲的结合模式。计算对接，解核磁共振实验，和 X 射线晶体学表明，从乙内酰脲 3 位出现的芳香亚结构占据与香豆素环相同的 LC 结合位点。值得注意的是，乙内酰脲环延伸到香豆素命中所绘制的结合位点之外。乙内酰脲环同时与两个 LC 单体形成氢键。乙内酰脲 5 位的烷基亚结构部分占据靠近香豆素亚结构占据的口袋的新型结合口袋。总体而言，乙内酰脲结构数据表明，LC 可变结构域-可变结构域二聚体界面的更大区域比以前证明的更适合小分子结合，这将有助于开发更有效的全长 LC 动力学稳定剂。乙内酰脲环延伸到香豆素命中所绘制的结合位点之外。乙内酰脲环同时与两个 LC 单体形成氢键。乙内酰脲 5 位的烷基亚结构部分占据靠近香豆素亚结构占据的口袋的新型结合口袋。总体而言，乙内酰脲结构数据表明，LC 可变结构域-可变结构域二聚体界面的更大区域比以前证明的更适合小分子结合，这将有助于开发更有效的全长 LC 动力学稳定剂。乙内酰脲环延伸到香豆素命中所绘制的结合位点之外。乙内酰脲环同时与两个 LC 单体形成氢键。乙内酰脲 5 位的烷基亚结构部分占据靠近香豆素亚结构占据的口袋的新型结合口袋。总体而言，乙内酰脲结构数据表明，LC 可变结构域-可变结构域二聚体界面的更大区域比以前证明的更适合小分子结合，这将有助于开发更有效的全长 LC 动力学稳定剂。乙内酰脲 5 位的烷基亚结构部分占据靠近香豆素亚结构占据的口袋的新型结合口袋。总体而言，乙内酰脲结构数据表明，LC 可变结构域-可变结构域二聚体界面的更大区域比以前证明的更适合小分子结合，这将有助于开发更有效的全长 LC 动力学稳定剂。乙内酰脲 5 位的烷基亚结构部分占据靠近香豆素亚结构占据的口袋的新型结合口袋。总体而言，乙内酰脲结构数据表明，LC 可变结构域-可变结构域二聚体界面的更大区域比以前证明的更适合小分子结合，这将有助于开发更有效的全长 LC 动力学稳定剂。