Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria 3086, Australia.
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia.
Int J Mol Sci. 2019 May 7;20(9):2234. doi: 10.3390/ijms20092234.
Interactions between the pro-survival and pro-apoptotic members of the Bcl-2 family of proteins dictate whether a cell lives or dies. Much of our knowledge of the molecular details of these interactions has come from biochemical and structural studies on the pro-survival protein Bcl-x. The first high-resolution structure of any Bcl-2 family member was of Bcl-x, which revealed the conserved topology amongst all family members. Subsequent structures of Bcl-x complexes with pro-apoptotic ligands demonstrated the general features of all pro-survival:pro-apoptotic complexes. Structural studies involving Bcl-x were also the basis for the discovery of the first small-molecule pro-survival protein inhibitors, leading ultimately to the development of a new class of drugs now successfully used for cancer treatment in the clinic. This article will review our current knowledge of the structural biology of Bcl-x and how this has impacted our understanding of the molecular details of the intrinsic apoptotic pathway.
Bcl-2 家族蛋白的生存促进和凋亡促进成员之间的相互作用决定了细胞的生死。我们对这些相互作用的分子细节的大部分了解都来自于对生存促进蛋白 Bcl-x 的生化和结构研究。第一个 Bcl-2 家族成员的高分辨率结构是 Bcl-x，它揭示了所有家族成员之间的保守拓扑结构。随后，Bcl-x 与凋亡促进配体的复合物结构显示了所有生存促进：凋亡促进复合物的一般特征。涉及 Bcl-x 的结构研究也是发现第一种小分子生存促进蛋白抑制剂的基础，最终导致开发了一类新的药物，目前在临床上成功用于癌症治疗。本文将回顾我们目前对 Bcl-x 的结构生物学的了解，以及这如何影响我们对内在凋亡途径的分子细节的理解。
