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Crystal structures of human calcineurin and the human FKBP12–FK506–calcineurin complex

Nature volume 378, pages 641–644 (1995)Cite this article

Abstract

CALCINEURIN (CaN) is a calcium- and ca 1modulin-dependent protein serine/threonine phosphatase which is critical for several important cellular processes, including T-cell activation1. CaN is the target of the immunosuppressive drugs cyclosporin A and FK506, which inhibit CaN after forming complexes with cyto-plasmic binding proteins (cyclophilin and FKBP12, respectively)2. We report here the crystal structures of full-length human CaN at 2.1 Å resolution and of the complex of human CaN with FKBP12-FK506 at 3.5 Å resolution. In the native CaN structure, an auto-inhibitory 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 calcineurin, including a natural anchoring protein.

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  1. J. Ernest Villafranca: To whom correspondence should be addressed.

Authors and Affiliations

  1. Agouron Pharmaceuticals Inc., 3565 General Atomics Court, San Diego, California, 92121-1121, USA

    Charles R. Kissinger, Hans E. Parge, Daniel R. Knighton, Cristina T. Lewis, Laura A. Pelletier, Anna Tempczyk, Vincent J. Kalish, Kathleen D. Tucker, Richard E. Showalter, Ellen W. Moomaw, Louis N. Gastinel, Noriyuki Habuka, Xinghai Chen, Fausto Maldonado, John E. Barker, Russell Bacquet & J. Ernest Villafranca

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  1. Charles R. Kissinger
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Kissinger, C., Parge, H., Knighton, D. et al. Crystal structures of human calcineurin and the human FKBP12–FK506–calcineurin complex. Nature 378, 641–644 (1995). https://doi.org/10.1038/378641a0

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