Department of Pharmacology, Case Western Reserve University, Cleveland, OH, 44106, USA.
Department of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA.
Nat Commun. 2023 Feb 11;14(1):784. doi: 10.1038/s41467-023-36463-7.
15-prostaglandin dehydrogenase (15-PGDH) is a negative regulator of tissue stem cells that acts via enzymatic activity of oxidizing and degrading PGE2, and related eicosanoids, that support stem cells during tissue repair. Indeed, inhibiting 15-PGDH markedly accelerates tissue repair in multiple organs. Here we have used cryo-electron microscopy to solve the solution structure of native 15-PGDH and of 15-PGDH individually complexed with two distinct chemical inhibitors. These structures identify key 15-PGDH residues that mediate binding to both classes of inhibitors. Moreover, we identify a dynamic 15-PGDH lid domain that closes around the inhibitors, and that is likely fundamental to the physiologic 15-PGDH enzymatic mechanism. We furthermore identify two key residues, F185 and Y217, that act as hinges to regulate lid closing, and which both inhibitors exploit to capture the lid in the closed conformation, thus explaining their sub-nanomolar binding affinities. These findings provide the basis for further development of 15-PGDH targeted drugs as therapeutics for regenerative medicine.
15-前列腺素脱氢酶（15-PGDH）是组织干细胞的负调控因子，通过氧化和降解 PGE2 及相关类二十烷酸的酶活性发挥作用，在组织修复过程中支持干细胞。事实上，抑制 15-PGDH 可显著加速多个器官的组织修复。在这里，我们使用低温电子显微镜解决了天然 15-PGDH 及其与两种不同化学抑制剂分别复合的溶液结构。这些结构确定了介导与两类抑制剂结合的关键 15-PGDH 残基。此外，我们确定了一个动态的 15-PGDH 盖域，它围绕抑制剂关闭，这对于生理 15-PGDH 酶机制可能是基本的。我们还确定了两个关键残基 F185 和 Y217，它们作为铰链调节盖子的关闭，而这两个抑制剂都利用它们将盖子捕获在关闭构象中，从而解释了它们亚纳摩尔的结合亲和力。这些发现为进一步开发 15-PGDH 靶向药物作为再生医学的治疗方法提供了基础。
