Corticosteroid-binding globulin, a structural basis for steroid transport and proteinase-triggered release
Corticosteroid-binding globulin, a structural basis for steroid transport and proteinase-triggered release
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DOI：
10.1074/jbc.m705014200
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发表时间：
2007-10-05
影响因子：
4.8
通讯作者：
Muller, Yves A.
中科院分区：
文献类型：
--
作者：
Klieber, Michael A.;Underhill, Caroline;Muller, Yves A.
皮质类固醇结合球蛋白（CBG）是丝氨酸蛋白酶抑制剂（serpin）家族成员，在血液中转运糖皮质激素并调节其进入靶细胞。大鼠CBG的1.9埃晶体结构表明其类固醇结合位点类似于相关丝氨酸蛋白酶抑制剂、甲状腺素结合球蛋白中的甲状腺素结合位点，并且诱变研究已经证实了构成类固醇结合口袋的关键残基的贡献。与甲状腺素结合的甲状腺素结合球蛋白不同，皮质醇结合的CBG显示“活性”丝氨酸蛋白酶抑制剂构象，蛋白酶敏感的反应中心环（RCL）完全从调节β-折叠A中排出。此外，CBG结构使我们能够预测，蛋白水解切割的RCL完全插入丝氨酸蛋白酶抑制剂折叠发生在与位移和螺旋D的解旋，这将破坏类固醇结合位点。RCL定位和CBG类固醇结合位点的占用之间的这种变构偶联，其类似于凝血酶抑制性丝氨酸蛋白酶抑制剂肝素辅因子II和抗凝血酶RCL的配体（糖胺聚糖）依赖性活化，确保了靶蛋白酶对CBG的最佳识别和类固醇向作用位点的有效释放。
Corticosteroid-binding globulin (CBG) is a serine proteinase inhibitor (serpin) family member that transports glucocorticoids in blood and regulates their access to target cells. The 1.9 angstrom crystal structure of rat CBG shows that its steroid-binding site resembles the thyroxin-binding site in the related serpin, thyroxin-binding globulin, and mutagenesis studies have confirmed the contributions of key residues that constitute the steroid-binding pocket. Unlike thyroxin-bound thyroxin-binding globulin, the cortisol-bound CBG displays an "active" serpin conformation with the proteinase-sensitive, reactive center loop (RCL) fully expelled from the regulatory beta-sheet A. Moreover, the CBG structure allows us to predict that complete insertion of the proteolytically cleaved RCL into the serpin fold occurs in concert with a displacement and unwinding of helix D that would disrupt the steroid-binding site. This allosteric coupling between RCL positioning and occupancy of the CBG steroid-binding site, which resembles the ligand (glycosamino-glycan)dependent activation of the thrombin inhibitory serpins heparin cofactor II and anti-thrombin RCLs, ensures both optimal recognition of CBG by target proteinases and efficient release of steroid to sites of action.