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被亲免素-免疫抑制剂FKBP12-FK506复合物抑制的钙调神经磷酸酶的X射线结构。

X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex.

作者信息

Griffith J P, Kim J L, Kim E E, Sintchak M D, Thomson J A, Fitzgibbon M J, Fleming M A, Caron P R, Hsiao K, Navia M A

机构信息

Vertex Pharmaceuticals, Incorporated, Cambridge, Massachusetts 02139-4211, USA.

出版信息

Cell. 1995 Aug 11;82(3):507-22. doi: 10.1016/0092-8674(95)90439-5.

Abstract

The X-ray structure of the ternary complex of a calcineurin A fragment, calcineurin B, FKBP12, and the immunosuppressant drug FK506 (also known as tacrolimus) has been determined at 2.5 A resolution, providing a description of how FK506 functions at the atomic level. In the structure, the FKBP12-FK506 binary complex does not contact the phosphatase active site on calcineurin A that is more than 10 A removed. Instead, FKBP12-FK506 is so positioned that it can inhibit the dephosphorylation of its macromolecular substrates by physically hindering their approach to the active site. The ternary complex described here represents the three-dimensional structure of a Ser/Thr protein phosphatase and provides a structural basis for understanding calcineurin inhibition by FKBP12-FK506.

摘要

钙调神经磷酸酶A片段、钙调神经磷酸酶B、FKBP12和免疫抑制剂药物FK506(也称为他克莫司)的三元复合物的X射线结构已在2.5埃分辨率下确定,这为FK506在原子水平上的作用方式提供了描述。在该结构中,FKBP12 - FK506二元复合物不与钙调神经磷酸酶A上距离超过10埃的磷酸酶活性位点接触。相反,FKBP12 - FK506的位置使其能够通过物理阻碍其大分子底物接近活性位点来抑制其去磷酸化。这里描述的三元复合物代表了一种丝氨酸/苏氨酸蛋白磷酸酶的三维结构,并为理解FKBP12 - FK506对钙调神经磷酸酶的抑制作用提供了结构基础。

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