Abstract：
Cancer cells bypass cell death by changing the expression of the BCL-2 family of proteins, which are apoptotic pathway regulators. Upregulation of pro-survival BCL-2 proteins or downregulation of cell death effectors BAX and BAK interferes with the initiation of the intrinsic apoptotic pathway. In normal cells, apoptosis can occur through pro-apoptotic BH3-only proteins interacting and inhibiting pro-survival BCL-2 proteins. When cancer cells over-express pro-survival BCL-2 proteins, a potential remedy is the sequestration of these pro-survival proteins through a class of anti-cancer drugs called BH3 mimetics that bind in the hydrophobic groove of pro-survival BCL-2 proteins. To improve the design of these BH3 mimetics, the packing interface between BH3 domain ligands and pro-survival BCL-2 proteins was analyzed using the Knob-Socket model to identify the amino acid residues responsible for interaction affinity and specificity. A Knob-Socket analysis organizes all the residues in a binding interface into simple 4 residue units: 3-residue sockets defining surfaces on a protein that pack a 4th residue knob from the other protein. In this way, the position and composition of the knobs packing into sockets across the BH3/BCL-2 interface can be classified. A Knob-Socket analysis of 19 BCL-2 protein and BH3 helix co-crystals reveal multiple conserved binding patterns across protein paralogs. Conserved knob residues such as a Gly, Leu, Ala and Glu most likely define binding specificity in the BH3/BCL-2 interface, whereas other residues such as Asp, Asn, and Val are important for forming surface sockets that bind these knobs. These findings can be used to inform the design of BH3 mimetics that are specific to pro-survival BCL-2 proteins for cancer therapeutics.
摘要：
癌细胞通过改变BCL-2家族蛋白的表达绕过细胞死亡，它们是凋亡途径调节因子。促存活BCL-2蛋白的上调或细胞死亡效应子BAX和BAK的下调会干扰内在凋亡途径的启动。在正常细胞中,凋亡可以通过促凋亡BH3蛋白相互作用和抑制促存活BCL-2蛋白而发生。当癌细胞过度表达促存活BCL-2蛋白时，一个潜在的治疗方法是通过一类称为BH3模拟物的抗癌药物来隔离这些促存活蛋白,这些药物结合在促存活BCL-2蛋白的疏水槽中.为了改进这些BH3模拟物的设计，使用Knob-Socket模型分析了BH3结构域配体和促存活BCL-2蛋白之间的包装界面,以鉴定负责相互作用亲和力和特异性的氨基酸残基.Knob-Socket分析将结合界面中的所有残基组织成简单的4个残基单元：3个残基的插座定义了蛋白质上的表面，该蛋白质包装了来自其他蛋白质的第4个残基旋钮。这样,可以对BH3/BCL-2接口上装入插座的旋钮的位置和组成进行分类。19个BCL-2蛋白和BH3螺旋共晶的Knob-Socket分析揭示了蛋白质旁系同源物之间的多种保守结合模式。保守的旋钮残基，如Gly，Leu,Ala和Glu最有可能定义BH3/BCL-2界面的结合特异性，而其他残基如Asp，Asn,和Val对于形成结合这些旋钮的表面插座很重要。这些发现可用于告知BH3模拟物的设计,所述BH3模拟物对用于癌症治疗的促存活BCL-2蛋白具有特异性。
