Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Adv Exp Med Biol. 2010;680:481-8. doi: 10.1007/978-1-4419-5913-3_54.
The inactive porphobilinogen synthase (PBGS) hexamer has an oligomer-specific and phylogenetically variable surface cavity that is not present in the active octamer. The octamer and hexamer are components of a dynamic quaternary structure equilibrium characteristic of morpheeins. Small molecules that bind to the hexamer-specific surface cavity, which is at the interface of three subunits, are predicted to act as allosteric inhibitors that function by drawing the oligomeric equilibrium toward the hexamer. We used GLIDE as a tool to enrich a 250,000 molecule library for molecules with enhanced probability of acting as hexamer-stabilizing allosteric inhibitors of PBGS from Yersinia enterocolitica. Eighty-six compounds were tested in vitro and five showed hexamer stabilization. We discuss the application of computational docking to surface cavities as an approach to find allosteric modulators of protein function with specific reference to morpheeins that function as an equilibrium of non-additive quaternary structure assemblies.
无活性的卟胆原合酶（PBGS）六聚体具有一个寡聚体特异性和系统发育上可变的表面腔，该表面腔不存在于活性八聚体中。八聚体和六聚体是 morpheeins 特征的动态四级结构平衡的组成部分。预测与位于三个亚基界面的六聚体特异性表面腔结合的小分子将作为别构抑制剂发挥作用，通过将寡聚平衡拉向六聚体来发挥作用。我们使用 GLIDE 作为工具，从肠炎沙门氏菌中对具有增强作为 PBGS 六聚体稳定的别构抑制剂的可能性的 250,000 种分子文库进行了富集。在体外测试了 86 种化合物，其中 5 种显示出六聚体稳定性。我们讨论了将计算对接应用于表面腔作为寻找蛋白质功能别构调节剂的方法，特别参考了作为非加和四级结构组装平衡的 morpheeins。
