Chai J, Shiozaki E, Srinivasula S M, Wu Q, Datta P, Alnemri E S, Shi Y
Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Washington Road, Princeton, NJ 08544, USA.
Cell. 2001 Mar 9;104(5):769-80. doi: 10.1016/s0092-8674(01)00272-0.
The inhibitor of apoptosis (IAP) proteins suppress cell death by inhibiting the catalytic activity of caspases. Here we present the crystal structure of caspase-7 in complex with a potent inhibitory fragment from XIAP at 2.45 A resolution. An 18-residue XIAP peptide binds the catalytic groove of caspase-7, making extensive contacts to the residues that are essential for its catalytic activity. Strikingly, despite a reversal of relative orientation, a subset of interactions between caspase-7 and XIAP closely resemble those between caspase-7 and its tetrapeptide inhibitor DEVD-CHO. Our biochemical and structural analyses reveal that the BIR domains are dispensable for the inhibition of caspase-3 and -7. This study provides a structural basis for the design of the next-generation caspase inhibitors.
凋亡抑制蛋白（IAP）通过抑制半胱天冬酶的催化活性来抑制细胞死亡。在此，我们展示了与XIAP的一个强效抑制片段形成复合物的半胱天冬酶-7的晶体结构，分辨率为2.45埃。一个18个残基的XIAP肽结合到半胱天冬酶-7的催化凹槽，与对其催化活性至关重要的残基进行广泛接触。引人注目的是，尽管相对方向相反，但半胱天冬酶-7与XIAP之间的一部分相互作用与半胱天冬酶-7与其四肽抑制剂DEVD-CHO之间的相互作用非常相似。我们的生化和结构分析表明，BIR结构域对于抑制半胱天冬酶-3和-7并非必需。这项研究为下一代半胱天冬酶抑制剂的设计提供了结构基础。
