Structural basis for the inhibition of caspase-3 by XIAP
Structural basis for the inhibition of caspase-3 by XIAP
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DOI：
10.1016/s0092-8674(01)00274-4
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发表时间：
2001-03-09
期刊：
影响因子：
64.5
通讯作者：
Salvesen, GS
中科院分区：
文献类型：
--
作者：
Riedl, SJ;Renatus, M;Salvesen, GS
通过半胱天冬酶抑制调节细胞凋亡的分子机制仍然知之甚少。主要的内源性抑制剂是IAP家族的成员，并以XIAP为例，XIAP调节启动子半胱天冬酶-9和执行子半胱天冬酶-3和-7。我们报告了XIAP的第二个BIR结构域（BIR 2）与caspase-3复合的晶体结构，分辨率为2.7埃，揭示了抑制的结构基础。该抑制剂通过其BIR结构域与酶表面进行有限的接触，并且与胱天蛋白酶-3的大多数接触源自N-末端延伸。这横跨底物结合裂缝，但与底物结合相比处于相反取向。抑制机制是由于抑制底物结合的空间位阻，并且与合成底物类似物抑制剂所利用的机制不同。
The molecular mechanism(s) that regulate apoptosis by caspase inhibition remain poorly understood. The main endogenous inhibitors are members of the IAP family and are exemplified by XIAP, which regulates the initiator caspase-9, and the executioner caspases-3 and -7. We report the crystal structure of the second BIR domain of XIAP (BIR2) in complex with caspase-3, at a resolution of 2.7 Angstrom, revealing the structural basis for inhibition. The inhibitor makes limited contacts through its BIR domain to the surface of the enzyme, and most contacts to caspase-3 originate from the N-terminal extension. This lies across the substrate binding cleft, but in reverse orientation compared to substrate binding. The mechanism of inhibition is due to a steric blockade prohibitive of substrate binding, and is distinct from the mechanism utilized by synthetic substrate analog inhibitors.