Structural and functional insights into aldosterone synthase interaction with its redox partner protein adrenodoxin.
Structural and functional insights into aldosterone synthase interaction with its redox partner protein adrenodoxin.
复制标题
DOI：
10.1016/j.jbc.2021.100794
复制
发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Scott EE
中科院分区：
文献类型：
--
作者：
Brixius-Anderko S;Scott EE
醛固酮是人体内控制血压和盐分平衡的主要矿化皮质激素。醛固酮的过量产生导致原发性醛固酮增多症，这是继发性高血压最常见的形式，治疗方案有限。细胞色素P450 11B2 （CYP11B2，醛固酮合成酶）产生醛固酮需要铁/硫蛋白肾上腺素所传递的电子进行两次还原。关于肾上腺素还蛋白/CYP11B2相互作用的结构和功能基础的信息非常有限，这阻碍了原发性醛固酮增多症新治疗方案的发展。我们进行了一项系统的研究，以确定肾上腺素还毒素与CYP11B2的相互作用除了电子转移外，是否还具有变弹性成分。事实上，肾上腺素浓度的局部增加促进了底物11-脱氧皮质酮与活性部位的抑制剂奥西洛他汀（LCI699）在17 Å以外的结合，并增强了后者的抑制作用。CYP11B2与肾上腺素还氧素复合物的结构在蛋白-蛋白界面上通过5个盐桥和4个氢键相互作用确定了特异性残基。与代谢胆固醇的CYP11A1和产生皮质醇的CYP11B1（也结合肾上腺素还毒素）比较，揭示了这些区域的结构差异。不同P450与肾上腺素还毒素相互作用的结构和功能差异可能为特异性靶向CYP11B2与肾上腺素还毒素相互作用的正交治疗原发性醛固酮增多症提供有价值的线索。
Aldosterone is the major mineralocorticoid in the human body controlling blood pressure and salt homeostasis. Overproduction of aldosterone leads to primary aldosteronism, which is the most common form of secondary hypertension with limited treatment options. Production of aldosterone by cytochrome P450 11B2 (CYP11B2, aldosterone synthase) requires two reduction events with the electrons delivered by the iron/sulfur protein adrenodoxin. Very limited information is available about the structural and functional basis of adrenodoxin/CYP11B2 interaction, which impedes the development of new treatment options for primary aldosteronism. A systematic study was carried out to determine if adrenodoxin interaction with CYP11B2 might also have an allosteric component in addition to electron transfer. Indeed, local increases in adrenodoxin concentration promote binding of the substrate 11-deoxycorticosterone and the inhibitor osilodrostat (LCI699) in the active site—over 17 Å away—as well as enhance the inhibitory effect of this latter drug. The CYP11B2 structure in complex with adrenodoxin identified specific residues at the protein–protein interface interacting via five salt bridges and four hydrogen bonds. Comparisons with cholesterol-metabolizing CYP11A1 and cortisol-producing CYP11B1, which also bind adrenodoxin, revealed substantial structural differences in these regions. The structural and functional differences between different P450 interactions with adrenodoxin may provide valuable clues for an orthogonal treatment approach for primary aldosteronism by specifically targeting the interaction between CYP11B2 and adrenodoxin.
登录
查看更多内容
影响因子：
37.8
作者：
Birtcher, KK;Ballantyne, CM
通讯作者：
Ballantyne, CM
影响因子：
3.9
作者：
Godamudunage, Malika P.;Grech, Anne M.;Scott, Emily E.
通讯作者：
Scott, Emily E.
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
4.8
作者：
Mast, Natalia;Annalora, Andrew J.;Pikuleva, Irina A.
通讯作者：
Pikuleva, Irina A.
影响因子：
11.5
作者：
Duggan, Sean
通讯作者：
Duggan, Sean