CRYSTAL-STRUCTURES OF HUMAN CALCINEURIN AND THE HUMAN FKBP12-FK506-CALCINEURIN COMPLEX

被引：691

作者：

KISSINGER, CR ^{[1
]}

PARGE, HE ^{[1
]}

KNIGHTON, DR ^{[1
]}

LEWIS, CT ^{[1
]}

PELLETIER, LA ^{[1
]}

TEMPCZYK, A ^{[1
]}

KALISH, VJ ^{[1
]}

TUCKER, KD ^{[1
]}

SHOWALTER, RE ^{[1
]}

MOOMAW, EW ^{[1
]}

GASTINEL, LN ^{[1
]}

HABUKA, N ^{[1
]}

CHEN, XH ^{[1
]}

MALDONADO, F ^{[1
]}

BARKER, JE ^{[1
]}

BACQUET, R ^{[1
]}

VILLAFRANCA, JE ^{[1
]}

机构：

[1] AGOURON PHARMACEUT INC,SAN DIEGO,CA 92121

来源：

NATURE | 1995年 / 378卷 / 6557期

关键词：

D O I：

10.1038/378641a0

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：641 / 644

页数：4

共 29 条

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