Liu Z, Sun C, Olejniczak E T, Meadows R P, Betz S F, Oost T, Herrmann J, Wu J C, Fesik S W
Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Nature. 2000;408(6815):1004-8. doi: 10.1038/35050006.
The inhibitor-of-apoptosis proteins (IAPs) regulate programmed cell death by inhibiting members of the caspase family of enzymes. Recently, a mammalian protein called Smac (also named DIABLO) was identified that binds to the IAPs and promotes caspase activation. Although undefined in the X-ray structure, the amino-terminal residues of Smac are critical for its function. To understand the structural basis for molecular recognition between Smac and the IAPs, we determined the solution structure of the BIR3 domain of X-linked IAP (XIAP) complexed with a functionally active nine-residue peptide derived from the N terminus of Smac. The peptide binds across the third beta-strand of the BIR3 domain in an extended conformation with only the first four residues contacting the protein. The complex is stabilized by four intermolecular hydrogen bonds, an electrostatic interaction involving the N terminus of the peptide, and several hydrophobic interactions. This structural information, along with the binding data from BIR3 and Smac peptide mutants reported here, should aid in the design of small molecules that may be used for the treatment of cancers that overexpress IAPs.
凋亡抑制蛋白（IAPs）通过抑制半胱天冬酶家族的酶来调节程序性细胞死亡。最近，一种名为Smac（也称为DIABLO）的哺乳动物蛋白被鉴定出来，它能与IAPs结合并促进半胱天冬酶的激活。尽管Smac的X射线结构尚未明确，但它的氨基末端残基对其功能至关重要。为了了解Smac与IAPs之间分子识别的结构基础，我们确定了与来自Smac N末端的具有功能活性的九肽复合的X连锁凋亡抑制蛋白（XIAP）的BIR3结构域的溶液结构。该肽以伸展构象跨BIR3结构域的第三条β链结合，只有前四个残基与蛋白质接触。该复合物通过四个分子间氢键、一个涉及肽N末端的静电相互作用以及几个疏水相互作用得以稳定。这些结构信息，以及本文报道的BIR3和Smac肽突变体的结合数据，应该有助于设计可用于治疗IAPs过表达癌症的小分子。
