Conformational flexibility in mammalian 15S-lipoxygenase: Reinterpretation of the crystallographic data
Conformational flexibility in mammalian 15S-lipoxygenase: Reinterpretation of the crystallographic data
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DOI：
10.1002/prot.21590
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发表时间：
2008-02-15
影响因子：
2.9
通讯作者：
Shin, Whanchul
中科院分区：
文献类型：
--
作者：
Choi, Jongkeun;Chon, Jae Kyung;Shin, Whanchul
脂氧合酶（Lipoxygenases，LOX）是一类非血红素铁双加氧酶家族，催化多不饱和脂肪酸的区域选择性和立体选择性过氧化反应，参与多种炎症性疾病和癌症的发生。Gillmor等在1997年报道的兔15 S-LOX 1的晶体结构对于理解哺乳动物LOXs的性质起着关键作用。在这种结构中，包括表面α 2螺旋中的12个残基在内的三个片段缺失，通常被描述为“无序的”。“通过重新解释原始晶体学数据，我们能够阐明分子的两种不同构象，两者都具有良好的α 2螺旋。令人惊讶的是，一个分子含有抑制剂，另一个分子没有，从而分别采用封闭和开放形式。它们在原始结构中不存在的片段的构象上不同，这通过α 2的12 A运动来突出显示。因此，它们显示出底物结合腔的大小和形状的差异。新的模型应该提供新的洞察力的催化机制，涉及诱导的结合口袋的构象变化。这也可能有助于LOX抑制剂的结构设计。
Lipoxygenases (LOXs) are a family of non-heme iron dioxygenases that catalyze the regioselective and stereospecific hydroperoxidation of polyunsaturated fatty acids, and are involved in a variety of inflammatory diseases and cancers. The crystal structure of rabbit 15S-LOX1 that was reported by Gillmor et al. in 1997 has played key roles for understanding the properties of mammalian LOXs. In this structure, three segments, including 12 residues in the superficial alpha 2 helix, are absent and have usually been described as "disordered." By reinterpreting the original crystallographic data we were able to elucidate two different conformations of the molecule, both having well ordered a2 helices. Surprisingly, one molecule contained an inhibitor and the other did not, thereby adopting a closed and an open form, respectively. They differed in the conformation of the segments that were absent in the original structure, which is highlighted by a 12 A movement of alpha 2. Consequently, they showed a difference in the size and shape of the substrate-binding cavity. The new model should provide new insight into the catalytic mechanism involving induced conformational change of the binding pocket. It may also be helpful for the structure-based design of LOX inhibitors.