6KEY

Structural basis for the regulation of inducible nitric oxide synthase (iNOS) by the SPRY domain-containing SOCS box protein 2 (SPSB2)

6KEY の概要

• エントリーDOI: 10.2210/pdb6key/pdb
• 分子名称: SPRY domain-containing SOCS box protein 2, Nitric oxide synthase, inducible (3 entities in total)
• 機能のキーワード: spry domain-containing socs box protein, spsb2, inducible nitric oxide synthase, inos, e3 ubiquitin ligase, protein binding-inhibitor complex, protein binding/inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 23971.78

構造登録者

Li, K.,Kuang, Z. (登録日: 2019-07-05, 公開日: 2020-07-01, 最終更新日: 2024-03-27)

主引用文献

Li, K.,You, T.,Zhao, P.,Luo, Y.,Zhang, D.,Wei, H.,Wang, Y.,Yang, J.,Guan, X.,Kuang, Z.
Structural basis for the regulation of inducible nitric oxide synthase by the SPRY domain-containing SOCS box protein SPSB2, an E3 ubiquitin ligase.
Nitric Oxide, 113-114:1-6, 2021

PubMed Abstract: Relatively high concentration of nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) in response to a variety of stimuli is a source of reactive nitrogen species, an important weapon of host innate immune defense. The SPRY domain-containing SOCS box protein 2 (SPSB2) is an E3 ubiquitin ligase that regulates the lifetime of iNOS. SPSB2 interacts with the N-terminal region of iNOS via a binding site on the SPRY domain of SPSB2, and recruits an E3 ubiquitin ligase complex to polyubiquitinate iNOS, leading to its proteasomal degradation. Although critical residues for the SPSB2-iNOS interaction have been identified, structural basis for the interaction remains to be explicitly determined. In this study, we have determined a crystal structure of the N-terminal region of iNOS in complex with the SPRY domain of SPSB2 at 1.24 Å resolution. We have resolved the roles of some flanking residues, whose contribution to the SPSB2-iNOS interaction was structurally unclear previously. Furthermore, we have evaluated the effects of SPSB2 inhibitors on NO production using transient transfection and cell-penetrating peptide approaches, and found that such inhibitors can elevate NO production in RAW264.7 macrophages. These results thus provide a useful basis for the development of potent SPSB2 inhibitors as well as recruiting ligands for proteolysis targeting chimera (PROTAC) design.

PubMed: 33862200
DOI: 10.1016/j.niox.2021.04.004

実験手法

X-RAY DIFFRACTION (1.24 Å)