Crystal structure of human type III 3α-hydroxysteroid dehydrogenase/bile acid binding protein complexed with NADP+ and ursodeoxycholate
Crystal structure of human type III 3α-hydroxysteroid dehydrogenase/bile acid binding protein complexed with NADP+ and ursodeoxycholate
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DOI：
10.1021/bi010919a
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发表时间：
2001-08-28
期刊：
影响因子：
2.9
通讯作者：
Lewis, M
中科院分区：
文献类型：
--
作者：
Jin, Y;Stayrook, SE;Lewis, M
显示了人III型3 α-羟基类固醇脱氢酶（HSD）/胆汁酸结合蛋白（AKR 1C 2）与NADP（+）和3 α，7 β-二羟基-5 β-胆烷酸（熊去氧胆酸盐）复合物在3.0 A分辨率下的晶体结构。因此，现在已经解决了醛酮还原酶超家族的人HSD成员的三维结构。AKR 1C 2与前列腺产生强效雄激素5 α-二氢睾酮和胆汁酸的肝脏转运有关。它还催化中枢神经系统中神经类固醇3 α-羟基-5 α-葡聚糖-20-酮的形成，氟西汀对其的变构调节与该药物用于经前抑郁有关。与超家族的其他成员一样，AKR 1C 2折叠成α/β-桶并以延伸构象结合NADP+。熊去氧胆酸盐的羧酸盐在活性位点的含氧阴离子孔中与AKR 1C 2结合。更有趣的是，熊去氧胆酸盐的方向基本上是“向后”和“颠倒”，从相关大鼠3 α-HSD中观察到的睾酮。NADP（+）。睾酮三元复合物，其中睾酮占据3-酮类固醇底物的位置。因此，熊去氧胆酸盐的取向与17 β-HSD底物的预期取向相似.三元结构解释了AKR 1C 2催化3 α-、17 β-和20 α-HSD反应的能力。AKR 1C 2的类固醇结合口袋与大鼠3 α-HSD的类固醇结合口袋的比较揭示了保守和非保守环残基的位置的显著差异，提供了对在所有人3 α-HSD同种型中观察到的但在大鼠同种型中没有观察到的功能灵活性的结构基础的了解。
The crystal structure of human type III 3 alpha -hydroxysteroid dehydrogenase (HSD)/bile acid binding protein (AKR1C2) complexed with NADP(+) and 3 alpha ,7 beta -dihydroxy-5 beta -cholanic acid (ursodeoxycholate) at 3.0 A resolution is presented. Thus, the three-dimensional structure has now been solved for a human HSD member of the aldo-keto reductase superfamily. AKR1C2 is implicated in the prostatic production of the potent androgen 5 alpha -dihydrotestosterone and the hepatic transport of bile acids. It also catalyzes the formation of the neurosteroid 3 alpha -hydroxy-5 alpha -pregnan-20-one in the central nervous system, and its allosteric modulation by fluoxetine has been linked to the use of this drug for premenstrual dsyphoria. Like other members of the superfamily, AKR1C2 folds into an alpha/beta -barrel and binds NADP+ in an extended conformation. The carboxylate of ursodeoxycholate binds to AKR1C2 in the oxyanion hole at the active site. More interestingly, the orientation of ursodeoxycholate is essentially "backwards" and "upside-down" from that observed for testosterone in the related rat 3 alpha -HSD . NADP(+). testosterone ternary complex, where testosterone assumes the position of a 3-ketosteroid substrate. The orientation of ursodeoxycholate is thus similar to that expected of a 17 beta -HSD substrate. The ternary structure explains the ability of AKR1C2 to catalyze 3 alpha-, 17 beta-, and 20 alpha -HSD reactions. Comparison of the steroid binding pocket of AKR1C2 with that of rat 3 alpha -HSD reveals significant differences in the positions of conserved and nonconserved loop residues, providing insights into the structural basis for the functional flexibility that is observed in all the human 3 alpha -HSD isoforms but not in the rat isoform.