Conformational similarity in the activation of caspase-3 and-7 revealed by the unliganded and inhibited structures of caspase-7
Conformational similarity in the activation of caspase-3 and-7 revealed by the unliganded and inhibited structures of caspase-7
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DOI：
10.1007/s10495-009-0388-9
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发表时间：
2009-10-01
期刊：
影响因子：
7.2
通讯作者：
Weber, Irene T.
中科院分区：
文献类型：
--
作者：
Agniswamy, Johnson;Fang, Bin;Weber, Irene T.
半胱天冬酶介导的细胞凋亡在正常细胞分化和衰老以及包括癌症、神经肌肉疾病和神经退行性疾病在内的许多疾病中具有重要作用。因此，半胱天冬酶活性和构象状态的调节具有治疗重要性。我们报道了一种新的非配体构象的caspase-7和抑制caspase-7与四肽Ac-YVAD-Cho的晶体结构。基于冗余凋亡执行者caspase-3和-7的非配体结构，已经提出了不同的构象状态和底物识别机制。目前的研究表明，刽子手caspase-3和-7具有相似的构象的unliganded的活性位点，以及走廊结合的活性位点。新的未配体的胱天蛋白酶-7结构表现出酪氨酸翻转机制，其中Tyr 230已经旋转以阻止进入S2结合位点，类似于未配体的胱天蛋白酶-3的活性位点构象。半胱天冬酶-7/YVAD的抑制结构表明，P4 Tyr结合的S4区特异性的极性残基的P4酰胺和半胱天冬酶-7 Gln 276的羰基氧之间的主链氢键的代价，这是类似于半胱天冬酶-3复合物。这种新的知识的结构和构象状态的unliganded和抑制半胱天冬酶将是重要的药物设计，以调节半胱天冬酶的活性和细胞凋亡。
Caspase-mediated apoptosis has important roles in normal cell differentiation and aging and in many diseases including cancer, neuromuscular disorders and neurodegenerative diseases. Therefore, modulation of caspase activity and conformational states is of therapeutic importance. We report crystal structures of a new unliganded conformation of caspase-7 and the inhibited caspase-7 with the tetrapeptide Ac-YVAD-Cho. Different conformational states and mechanisms for substrate recognition have been proposed based on unliganded structures of the redundant apoptotic executioner caspase-3 and -7. The current study shows that the executioner caspase-3 and -7 have similar conformations for the unliganded active site as well as the inhibitor-bound active site. The new unliganded caspase-7 structure exhibits the tyrosine flipping mechanism in which the Tyr230 has rotated to block entry to the S2 binding site similar to the active site conformation of unliganded caspase-3. The inhibited structure of caspase-7/YVAD shows that the P4 Tyr binds the S4 region specific to polar residues at the expense of a main chain hydrogen bond between the P4 amide and carbonyl oxygen of caspase-7 Gln 276, which is similar to the caspase-3 complex. This new knowledge of the structures and conformational states of unliganded and inhibited caspases will be important for the design of drugs to modulate caspase activity and apoptosis.