Crystal structures of zinc-free and -bound heme domain of human inducible nitric-oxide synthase - Implications for dimer stability and comparison with endothelial nitric-oxide synthase
Crystal structures of zinc-free and -bound heme domain of human inducible nitric-oxide synthase - Implications for dimer stability and comparison with endothelial nitric-oxide synthase
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DOI：
10.1074/jbc.274.30.21276
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发表时间：
1999-07-23
影响因子：
4.8
通讯作者：
Poulos, TL
中科院分区：
文献类型：
--
作者：
Li, HY;Raman, CS;Poulos, TL
人诱导型一氧化氮合酶（NOS-2）血红素结构域在无锌和锌结合状态下的晶体结构已被解决。在无锌结构中，两个与半胱氨酸相关的半胱氨酸残基形成二硫键。在锌结合状态下，这两个相同的半胱氨酸残基形成与内皮同种型（NOS-3）中观察到的锌-四硫醇盐（ZnS 4）中心不可区分的一部分。如在NOS-3中，ZnS 4在稳定亚基间接触和维持NOS-2的辅因子（四氢生物蝶呤）结合位点的完整性中起关键作用。NOS-2和NOS-3结构的比较说明了四级结构、三级拓扑结构以及底物和辅因子结合位点的保守性，此外还提供了对同种型特异性抑制剂设计的见解。结构比较还表明，蝶呤结合不优先稳定的二聚体界面的NOS-2的NOS-3。
The crystal structures of the heme domain of human inducible nitric-oxide synthase (NOS-2) in zinc-free and -bound states have been solved. In the zinc-free structure, two symmetry-related cysteine residues form a disulfide bond. In the zinc-bound state, these same two cysteine residues form part of a zinc-tetrathiolate (ZnS4) center indistinguishable from that observed in the endothelial isoform (NOS-3). As in NOS-3, ZnS4 plays a key role in stabilizing intersubunit contacts and in maintaining the integrity of the cofactor (tetrahydrobiopterin) binding site of NOS-2, A comparison of NOS-2 and NOS-3 structures illustrates the conservation of quaternary structure, tertiary topology, and substrate and cofactor binding sites, in addition to providing insights on isoform-specific inhibitor design. The structural comparison also reveals that pterin binding does not preferentially stabilize the dimer interface of NOS-2 over NOS-3.