Heller Gabriella T, Aprile Francesco A, Vendruscolo Michele
Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
Cell Mol Life Sci. 2017 Sep;74(17):3225-3243. doi: 10.1007/s00018-017-2563-4. Epub 2017 Jun 19.
It is generally recognized that a large fraction of the human proteome is made up of proteins that remain disordered in their native states. Despite the fact that such proteins play key biological roles and are involved in many major human diseases, they still represent challenging targets for drug discovery. A major bottleneck for the identification of compounds capable of interacting with these proteins and modulating their disease-promoting behaviour is the development of effective techniques to probe such interactions. The difficulties in carrying out binding measurements have resulted in a poor understanding of the mechanisms underlying these interactions. In order to facilitate further methodological advances, here we review the most commonly used techniques to probe three types of interactions involving small molecules: (1) those that disrupt functional interactions between disordered proteins; (2) those that inhibit the aberrant aggregation of disordered proteins, and (3) those that lead to binding disordered proteins in their monomeric states. In discussing these techniques, we also point out directions for future developments.
人们普遍认识到，人类蛋白质组的很大一部分是由在其天然状态下仍处于无序状态的蛋白质组成。尽管这类蛋白质发挥着关键的生物学作用，并与许多主要的人类疾病有关，但它们仍然是药物研发中具有挑战性的靶点。识别能够与这些蛋白质相互作用并调节其促病行为的化合物的一个主要瓶颈是开发探测此类相互作用的有效技术。进行结合测量的困难导致对这些相互作用背后的机制了解不足。为了促进进一步的方法学进展，我们在此回顾探测涉及小分子的三种类型相互作用最常用的技术：（1）破坏无序蛋白质之间功能相互作用的技术；（2）抑制无序蛋白质异常聚集的技术；（3）导致与单体状态的无序蛋白质结合的技术。在讨论这些技术时，我们还指出了未来的发展方向。
