GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom.
Protein Sci. 2013 Aug;22(8):1071-7. doi: 10.1002/pro.2298. Epub 2013 Jul 3.
ASK1, a member of the MAPK Kinase Kinase family of proteins has been shown to play a key role in cancer, neurodegeneration and cardiovascular diseases and is emerging as a possible drug target. Here we describe a 'replacement-soaking' method that has enabled the high-throughput X-ray structure determination of ASK1/ligand complexes. Comparison of the X-ray structures of five ASK1/ligand complexes from 3 different chemotypes illustrates that the ASK1 ATP binding site is able to accommodate a range of chemical diversity and different binding modes. The replacement-soaking system is also able to tolerate some protein flexibility. This crystal system provides a robust platform for ASK1/ligand structure determination and future structure based drug design.
ASK1 是丝裂原活化蛋白激酶激酶家族的一个成员，已被证明在癌症、神经退行性疾病和心血管疾病中发挥关键作用，并正在成为一个可能的药物靶点。在这里，我们描述了一种“取代浸泡”方法，该方法可实现高吞吐量的 ASK1/配体复合物的 X 射线结构测定。对来自 3 种不同化学类型的 5 种 ASK1/配体复合物的 X 射线结构进行比较，表明 ASK1 的 ATP 结合位点能够容纳多种化学多样性和不同的结合模式。替换浸泡系统也能够耐受一些蛋白质的灵活性。该晶体系统为 ASK1/配体结构测定和未来基于结构的药物设计提供了一个强大的平台。
