Structural characterization of nitric oxide synthase isoforms reveals striking active-site conservation
Structural characterization of nitric oxide synthase isoforms reveals striking active-site conservation
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DOI：
10.1038/6675
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发表时间：
1999-03-01
期刊：
影响因子：
--
通讯作者：
Weber, PC
中科院分区：
文献类型：
--
作者：
Fischmann, TO;Hruza, A;Weber, PC
人内皮型一氧化氮合酶（eNOS）和人诱导型一氧化氮合酶（iNOS）的催化结构域的晶体结构，解决了复杂的精氨酸底物和抑制剂S-乙基异硫脲（SEITU），分别。小分子结合在含有血红素和四氢生物蝶呤的较大活性位点空腔内的狭窄裂缝中。两者都与保守的谷氨酸（eNOS E361，iNOS E377）形成氢键。iNOS和eNOS的活性位点残基几乎相同。然而，结构比较提供了基础，设计同工酶选择性抑制剂。eNOS（2.4埃分辨率）和iNOS（2.25埃分辨率）的高分辨率、精细结构揭示了位于分子间界面处并由四个半胱氨酸（每个单体两个）配位的意想不到的结构锌。
Crystal structures of human endothelial nitric oxide synthase (eNOS) and human inducible NOS (iNOS) catalytic domains were solved in complex with the arginine substrate and an inhibitor S-ethylisothiourea (SEITU), respectively. The small molecules bind in a narrow cleft within the larger active-site cavity containing heme and tetrahydrobiopterin. Both are hydrogen-bonded to a conserved glutamate (eNOS E361, iNOS E377). The active-site residues of iNOS and eNOS ave nearly identical. Nevertheless, structural comparisons provide a basis for design of isozyme-selective inhibitors. The high-resolution, refined structures of eNOS (2.4 Angstrom resolution) and iNOS (2.25 Angstrom resolution) reveal an unexpected structural zinc situated at the intermolecular interface and coordinated by four cysteines, two from each monomer.