Muchmore S W, Sattler M, Liang H, Meadows R P, Harlan J E, Yoon H S, Nettesheim D, Chang B S, Thompson C B, Wong S L, Ng S L, Fesik S W
Protein Crystallography, Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Nature. 1996 May 23;381(6580):335-41. doi: 10.1038/381335a0.
THE Bcl-2 family of proteins regulate programmed cell death by an unknown mechanism. Here we describe the crystal and solution structures of a Bcl-2 family member, Bcl-xL (ref. 2). The structures consist of two central, primarily hydrophobic alpha-helices, which are surrounded by amphipathic helices. A 60-residue loop connecting helices alpha1 and alpha2 was found to be flexible and non-essential for anti-apoptotic activity. The three functionally important Bcl-2 homology regions (BH1, BH2 and BH3) are in close spatial proximity and form an elongated hydrophobic cleft that may represent the binding site for other Bcl-2 family members. The arrangement of the alpha-helices in Bcl-xL is reminiscent of the membrane translocation domain of bacterial toxins, in particular diphtheria toxin and the colicins. The structural similarity may provide a clue to the mechanism of action of the Bcl-2 family of proteins.
Bcl-2蛋白家族通过未知机制调节程序性细胞死亡。在此，我们描述了Bcl-2家族成员Bcl-xL的晶体结构和溶液结构（参考文献2）。这些结构由两个主要为疏水的中央α螺旋组成，周围环绕着两亲性螺旋。发现连接α1和α2螺旋的一个60个残基的环是灵活的，且对于抗凋亡活性并非必需。三个功能上重要的Bcl-2同源区域（BH1、BH2和BH3）在空间上紧密相邻，形成一个细长的疏水裂缝，可能代表其他Bcl-2家族成员的结合位点。Bcl-xL中α螺旋的排列让人联想到细菌毒素的膜转位结构域，特别是白喉毒素和大肠杆菌素。这种结构相似性可能为Bcl-2蛋白家族的作用机制提供线索。
