The potential use of single-particle electron microscopy as a tool for structure-based inhibitor design.
The potential use of single-particle electron microscopy as a tool for structure-based inhibitor design.
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DOI：
10.1107/s2059798317004077
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发表时间：
2017-06-01
期刊：
影响因子：
--
通讯作者：
Muench SP
中科院分区：
文献类型：
--
作者：
Rawson S;McPhillie MJ;Johnson RM;Fishwick CWG;Muench SP
电子显微镜的最新发展为基于结构的药物设计领域提供了新的机会。这篇综述展望了电子显微镜在这一领域的应用仍然存在的挑战和未来的前景。电子显微镜(EM)的最新发展使我们解决以前难以处理的体系的结构，特别是膜蛋白质和大的蛋白质复合体的能力发生了阶段性的变化。这为基于结构的药物设计领域提供了新的机会，一些高调的出版物解决了小分子和多肽抑制剂的结合位点。与更传统的X射线结晶学方法相比，EM有许多优点，例如可以分辨不同的构象状态，并允许在不受晶格约束的情况下更好地分辨体系的动力学。使用EM方法仍有重大挑战需要克服，尤其是结构确定的速度、低占有率配体的困难以及可用的适度分辨率。然而，随着EM领域的预期发展，EM成为基于结构的药物设计的关键工具的潜力似乎很有希望，通常是对X射线和核磁共振研究的补充。
Recent developments in electron microscopy have provided new opportunities in the field of structure-based drug design. This review looks at the challenges that remain and the future prospects for the use of electron microscopy in this area. Recent developments in electron microscopy (EM) have led to a step change in our ability to solve the structures of previously intractable systems, especially membrane proteins and large protein complexes. This has provided new opportunities in the field of structure-based drug design, with a number of high-profile publications resolving the binding sites of small molecules and peptide inhibitors. There are a number of advantages of EM over the more traditional X-ray crystallographic approach, such as resolving different conformational states and permitting the dynamics of a system to be better resolved when not constrained by a crystal lattice. There are still significant challenges to be overcome using an EM approach, not least the speed of structure determination, difficulties with low-occupancy ligands and the modest resolution that is available. However, with the anticipated developments in the field of EM, the potential of EM to become a key tool for structure-based drug design, often complementing X-ray and NMR studies, seems promising.