Crystal structure of the SPRY domain of human SPSB2 in the apo state
Crystal structure of the SPRY domain of human SPSB2 in the apo state
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apo 状态下人 SPSB2 SPRY 结构域的晶体结构
DOI：
10.1107/s2053230x1900623x
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Kuang Zhihe
中科院分区：
文献类型：
--
作者：
Luo Yanhong;Li kefa;Yang Jinjin;Zhang Danting;Zhou Yuying;Kuang Zhihe
含有 SPRY 结构域的 SOCS 盒蛋白 2 (SPSB2) 是四种哺乳动物 SPSB 蛋白之一，其特征是 C 端 SOCS 盒和中央 SPRY/B30.2 结构域。 SPSB2 通过 SPRY 结构域与诱导型一氧化氮合酶 (iNOS) 相互作用，并使 iNOS 多聚泛素化，导致其蛋白酶体降解。可以破坏 SPSB2-iNOS 相互作用并增加 NO 产生的抑制剂可以作为新型抗感染和抗癌药物。先前确定的鼠 SPSB2 结构可能无法反映 iNOS 结合位点的真实 apo 构象。此处，以 1.9 Å 的分辨率报道了 apo 状态下的人 SPSB2 SPRY 结构域的晶体结构。 apo 和配体结合结构的比较表明，iNOS 结合位点高度预先形成，并且配体结合时不会发生主要构象变化。此外，重组蛋白的 C 端 His6 标签与晶体相关 SPSB2 分子上 iNOS 结合位点附近的浅袋结合。这些发现可能有助于未来基于结构和基于片段的 SPSB2 抑制剂设计。
The SPRY domain-containing SOCS box protein 2 (SPSB2) is one of four mammalian SPSB proteins that are characterized by a C-terminal SOCS box and a central SPRY/B30.2 domain. SPSB2 interacts with inducible nitric oxide synthase (iNOS) via the SPRY domain and polyubiquitinates iNOS, resulting in its proteasomal degradation. Inhibitors that can disrupt SPSB2–iNOS interaction and augment NO production may serve as novel anti-infective and anticancer agents. The previously determined murine SPSB2 structure may not reflect the true apo conformation of the iNOS-binding site. Here, the crystal structure of human SPSB2 SPRY domain in the apo state is reported at a resolution of 1.9 Å. Comparison of the apo and ligand-bound structures reveals that the iNOS-binding site is highly preformed and that major conformational changes do not occur upon ligand binding. Moreover, the C-terminal His6 tag of the recombinant protein binds to a shallow pocket adjacent to the iNOS-binding site on a crystallographically related SPSB2 molecule. These findings may help in structure-based and fragment-based SPSB2 inhibitor design in the future.