X-RAY STRUCTURE OF A DECAMERIC CYCLOPHILIN CYCLOSPORINE CRYSTAL COMPLEX
X-RAY STRUCTURE OF A DECAMERIC CYCLOPHILIN CYCLOSPORINE CRYSTAL COMPLEX
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DOI：
10.1038/361091a0
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发表时间：
1993-01-07
期刊：
影响因子：
64.8
通讯作者：
WALKINSHAW, MD
中科院分区：
文献类型：
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作者：
PFLUGL, G;KALLEN, J;WALKINSHAW, MD
人亲环素A（CypA）是一种普遍存在的165个氨基酸的细胞内蛋白质，是环状十一肽免疫抑制剂药物环孢菌素A（CsA）1，2的主要受体，其预防移植手术后的同种异体移植物排斥3，4并且在自身免疫性疾病领域中有效5。CsA通过阻断导致白细胞介素-2转录的钙激活途径来防止T细胞增殖。除了它们结合CsA的能力之外，亲环素同种型6 -8还具有肽基-脯氨酰异构酶活性9 -11并提高蛋白质折叠速率12，13。大环内酯FK 506的作用与CsA相似，其同源受体FKBP也具有肽基脯氨酰异构酶活性14。单独抑制这种酶活性不足以实现免疫抑制15，16。药物-亲免蛋白复合物（CsA-CypA或FK 506-FKBP）和磷酸酶钙调神经磷酸酶之间的直接分子相互作用负责调节T细胞受体信号转导途径17，18。在这里，我们描述的十聚体CypA-CsA复合物的晶体结构。晶体学不对称单元由具有相当精确的非晶体学五重对称性的1：1亲环素-环孢菌素复合物的五聚体组成。2.8埃的电子密度图是高质量的。五个独立的环孢菌素分子是明确可识别的，提供了一个明确的图片之间的详细相互作用的肽药物和它的受体。它广泛地证实了以前的NMR，X射线和建模研究的结果，但提供了进一步的重要结构细节，这将是在设计的药物是CsA的类似物。
HUMAN cyclophilin A (CypA), a ubiquitous intracellular protein of 165 amino acids, is the major receptor for the cyclic undecapeptide immunosuppressant drug cyclosporin A (CsA)1,2, which pre vents allograft rejection after transplant surgery3,4 and is efficacious in the field of autoimmune diseases5. CsA prevents T-cell proliferation by blocking the calcium-activated pathway leading to interleukin-2 transcription. Besides their ability to bind CsA, the cyclophilin isoforms6-8 also have peptidyl-prolyl isomerase activity9-11 and enhance the rate of protein folding12,13. The macrolide FK506 acts similarly to CsA and its cognate receptor FKBP also has peptidyl-prolyl isomerase activity14. Inhibition of this enzymatic activity alone is not sufficient to achieve immunosuppression15,16. A direct molecular interaction between the drug-immunophilin complex (CsA-CypA, or FK506-FKBP) and the phosphatase calcineurin, is responsible for modulating the T-cell receptor signal transduction pathway17,18. Here we describe the crystal structure of a decameric CypA-CsA complex. The crystallographic asymmetric unit is composed of a pentamer of 1 : 1 cyclophilin-cyclosporin complexes of rather exact non-crystallographic fivefold symmetry. The 2.8 angstrom electron density map is of high quality. The five independent cyclosporin molecules are clearly identifiable, providing an unambiguous picture of the detailed interactions between a peptide drug and its receptor. It broadly confirms the results of previous NMR, X-ray and modelling studies, but provides further important structural details which will be of use in the design of drugs that are analogues of CsA.