Mcl-1-Bim complexes accommodate surprising point mutations via minor structural changes
Mcl-1-Bim complexes accommodate surprising point mutations via minor structural changes
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DOI：
10.1002/pro.329
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发表时间：
2010-03-01
期刊：
影响因子：
8
通讯作者：
Keating, Amy E.
中科院分区：
文献类型：
--
作者：
Fire, Emiko;Gulla, Stefano V.;Keating, Amy E.
Mcl-1是一种抗凋亡Bcl-2家族蛋白，可保护细胞免于死亡。Mcl-1和其他抗凋亡Bcl-2蛋白的结构揭示了某些促凋亡蛋白的α-螺旋BH 3区域可以结合的表面沟。尽管整体结构高度保守，但该沟的差异提供了对Bcl-2家族功能机制重要的结合特异性。我们报告的晶体结构的人Mcl-1绑定到一个BH 3肽来自人Bim和结构的三个配合物，以适应大的物理化学变化，在保守的Bim网站。突变对复合物稳定性具有令人惊讶的适度影响，并且结构表明Mcl-1可以经历小的变化以适应突变配体。例如，亮氨酸侧链的移位填充了由Bim BH 3的第一疏水掩埋位置处的异亮氨酸至丙氨酸突变留下的孔。还观察到更大的变化，其中螺旋α 3的移位在该相同位置处容纳异亮氨酸至酪氨酸突变。我们调查了可用的Mcl-1和Bcl-x（L）结构的变化，并观察到适度的灵活性，这可能是促进不同的仅BH 3蛋白与抗凋亡Bcl-2家族成员相互作用的关键。这些结构有助于我们对特异性如何实现的理解，并有助于指导靶向Mcl的新型抑制剂的设计，1.
Mcl-1 is an antiapoptotic Bcl-2-family protein that protects cells against death. Structures of Mcl-1, and of other anti-apoptotic Bcl-2 proteins, reveal a surface groove into which the alpha-helical BH3 regions of certain proapoptotic proteins can bind. Despite high overall structural conservation, differences in this groove afford binding specificity that is important for the mechanism of Bcl-2 family function. We report the crystal structure of human Mcl-1 bound to a BH3 peptide derived from human Bim and the structures for three complexes that accommodate large physicochemical changes at conserved Bim sites. The mutations had surprisingly modest effects on complex stability, and the structures show that Mcl-1 can undergo small changes to accommodate the mutant ligands. For example, a shift in a leucine side chain fills a hole left by an isoleucine-to-alanine mutation at the first hydrophobic buried position of Bim BH3. Larger changes are also observed, with shifting of helix alpha 3 accommodating an isoleucine-to-tyrosine mutation at this same position. We surveyed the variation in available Mcl-1 and Bcl-x(L) structures and observed moderate flexibility that is likely critical for facilitating interactions of diverse BH3-only proteins with I'll With the antiapoptotic Bcl-2 family members attracting significant attention as therapeutic targets, these structures contribute to our growing understanding of how specificity is achieved and can help to guide the design of novel inhibitors that target Mcl-1.