Riedl S J, Renatus M, Schwarzenbacher R, Zhou Q, Sun C, Fesik S W, Liddington R C, Salvesen G S
The Program in Apoptosis and Cell, Death Research, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Cell. 2001 Mar 9;104(5):791-800. doi: 10.1016/s0092-8674(01)00274-4.
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 A, 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.
通过抑制半胱天冬酶来调节细胞凋亡的分子机制仍知之甚少。主要的内源性抑制剂是凋亡抑制蛋白（IAP）家族成员，以X连锁凋亡抑制蛋白（XIAP）为代表，它调节起始半胱天冬酶-9以及执行半胱天冬酶-3和-7。我们报道了XIAP的第二个杆状病毒IAP重复序列结构域（BIR2）与半胱天冬酶-3复合物的晶体结构，分辨率为2.7埃，揭示了抑制作用的结构基础。抑制剂通过其BIR结构域与酶表面的接触有限，与半胱天冬酶-3的大多数接触源自N端延伸。它横跨底物结合裂隙，但与底物结合的方向相反。抑制机制是由于空间位阻阻碍了底物结合，这与合成底物类似物抑制剂所利用的机制不同。
