Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain
Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain
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DOI：
10.1038/35050006
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发表时间：
2000-12-21
期刊：
影响因子：
64.8
通讯作者：
Fesik, SW
中科院分区：
文献类型：
--
作者：
Liu, ZH;Sun, CH;Fesik, SW
细胞凋亡通道蛋白（IAP）（1）通过抑制半胱天冬酶家族的成员来调节程序性细胞死亡（2-5）。最近，一种名为Smac（6）（也称为DIABLO（7））的哺乳动物蛋白被鉴定出与IAP结合并促进半胱天冬酶激活。尽管在X射线结构中未定义，但Smac的氨基末端残基对其功能至关重要（8，9）。为了了解Smac和IAP之间分子识别的结构基础，我们确定了X-连接IAP（XIAP）的BIR 3结构域与来自Smac N末端的功能活性九残基肽复合的溶液结构。该肽以延伸构象结合BIR 3结构域的第三条β链，仅前四个残基接触蛋白质。该复合物通过四个分子间氢键、涉及肽的N末端的静电相互作用和几种疏水相互作用来稳定。该结构信息，沿着来自本文报道的BIR 3和Smac肽突变体的结合数据，应有助于设计可用于治疗过表达IAP的癌症的小分子（10-12）。
The inhibitor-of-apoptosis proteins (IAPs)(1) regulate programmed cell death by inhibiting members of the caspase family of enzymes(2-5). Recently, a mammalian protein called Smac(6) (also named DIABLO(7)) 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(8,9). 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(10-12).