CRYSTAL-STRUCTURES OF HUMAN CALCINEURIN AND THE HUMAN FKBP12-FK506-CALCINEURIN COMPLEX
CRYSTAL-STRUCTURES OF HUMAN CALCINEURIN AND THE HUMAN FKBP12-FK506-CALCINEURIN COMPLEX
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DOI：
10.1038/378641a0
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发表时间：
1995-12-07
期刊：
影响因子：
64.8
通讯作者：
VILLAFRANCA, JE
中科院分区：
文献类型：
--
作者：
KISSINGER, CR;PARGE, HE;VILLAFRANCA, JE
钙调神经磷酸酶（CaN）是一种钙和钙调蛋白依赖性蛋白丝氨酸/苏氨酸磷酸酶，对几个重要的细胞过程至关重要，包括T细胞活化（1）。CaN是免疫抑制药物环孢菌素A和FK 506的靶点，它们在与细胞质结合蛋白（分别为亲环蛋白和FKBP 12）形成复合物后抑制CaN（2）。我们在此报告了2.1埃分辨率的全长人CaN和3.5埃分辨率的人CaN与FKBP 12-FK 506的复合物的晶体结构。在天然CaN结构中，自抑制元件结合在含Zn/Fe的活性位点。的金属网站的几何形状和活性位点的水结构建议的催化机制，涉及亲核攻击的底物磷酸盐的金属活化的水分子。在FKBP 12-FK 506-CaN复合物中，自抑制元件从活性位点被置换。FKBP 12-FK 506的结合位点似乎与其他非竞争性钙调磷酸酶抑制剂（包括天然锚定蛋白）共享。
CALCINEURIN (CaN) is a calcium- and calmodulin-dependent protein serine/threonine phosphatase which is critical for several important cellular processes, including T-cell activation(1). CaN is the target of the immunosuppressive drugs cyclosporin A and FK506, which inhibit CaN after forming complexes with cytoplasmic binding proteins (cyclophilin and FKBP12, respectively)(2). We report here the crystal structures of full-length human CaN at 2.1 Angstrom resolution and of the complex of human CaN with FKBP12-FK506 at 3.5 Angstrom resolution. In the native CaN structure, an autoinhibitory element binds at the Zn/Fe-containing active site. The metal-site geometry and active-site water structure suggest a catalytic mechanism involving nucleophilic attack on the substrate phosphate by a metal-activated water molecule. In the FKBP12-FK506-CaN complex, the auto-inhibitory element is displaced from the active site. The site of binding of FKBP12-FK506 appears to be shared by other non-competitive inhibitors of calcine-urin, including a natural anchoring protein.