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首页> 美国卫生研究院文献>Antioxidants >Evidence for an Allosteric S-Nitrosoglutathione Binding Site in S-Nitrosoglutathione Reductase (GSNOR)
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Evidence for an Allosteric S-Nitrosoglutathione Binding Site in S-Nitrosoglutathione Reductase (GSNOR)

机译：S-硝基谷胱甘肽还原酶（GSNOR）中的变构S-硝基谷胱甘肽结合位点的证据。

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Current research has identified -nitrosoglutathione reductase (GSNOR) as the central enzyme for regulating protein -nitrosylation. In addition, the dysregulation of GSNOR expression is implicated in several organ system pathologies including respiratory, cardiovascular, hematologic, and neurologic, making GSNOR a primary target for pharmacological intervention. This study demonstrates the kinetic activation of GSNOR by its substrate -nitrosoglutathione (GSNO). GSNOR kinetic analysis data resulted in nonhyperbolic behavior that was successfully accommodated by the Hill–Langmuir equation with a Hill coefficient of +1.75, indicating that the substrate, GSNO, was acting as a positive allosteric affector. Docking and molecular dynamics simulations were used to predict the location of the GSNO allosteric domain comprising the residues Asn185, Lys188, Gly321, and Lys323 in the vicinity of the structural Zn -binding site. GSNO binding to Lys188, Gly321, and Lys323 was further supported by hydrogen–deuterium exchange mass spectroscopy (HDXMS), as deuterium exchange significantly decreased at these residues in the presence of GSNO. The site-directed mutagenesis of Lys188Ala and Lys323Ala resulted in the loss of allosteric behavior. Ultimately, this work unambiguously demonstrates that GSNO at large concentrations activates GSNOR by binding to an allosteric site comprised of the residues Asn185, Lys188, Gly321, and Lys323. The identification of an allosteric GSNO-binding domain on GSNOR is significant, as it provides a platform for pharmacological intervention to modulate the activity of this essential enzyme.
机译：目前的研究已确定-亚硝基谷胱甘肽还原酶（GSNOR）是调节蛋白质-亚硝基化的中心酶。此外，GSNOR表达失调还涉及多种器官系统病理，包括呼吸系统，心血管，血液和神经系统疾病，使GSNOR成为药物干预的主要靶标。这项研究证明了GSNOR被底物-亚硝基谷胱甘肽（GSNO）激活。 GSNOR动力学分析数据得出非双曲线行为，已成功通过Hill-Langmuir方程适应了Hill系数+1.75，这表明底物GSNO可作为正变构效应子。使用对接和分子动力学模拟来预测GSNO变构域的位置，该结构域包含残基Asn185，Lys188，Gly321和Lys323在结构锌结合位点附近。氢-氘交换质谱（HDXMS）进一步支持了GSNO与Lys188，Gly321和Lys323的结合，因为在存在GSNO的情况下，这些残基上的氘交换明显减少。 Lys188Ala和Lys323Ala的定点诱变导致变构行为的丧失。最终，这项工作明确地表明，高浓度的GSNO通过结合由Asn185，Lys188，Gly321和Lys323残基组成的变构位点来激活GSNOR。 GSNOR上的变构GSNO结合结构域的鉴定意义重大，因为它为药理学干预提供了调节该必需酶活性的平台。

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