• DOI:10.1038/378641A0
• Corpus ID: 4337105

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

@article{Kissinger1995CrystalSO,
  title={Crystal structures of human calcineurin and the human FKBP12–FK506–calcineurin complex},
  author={Charles Kissinger and Hans E. Parge and Daniel R. Knighton and Cristina T. Lewis and Laura A. Pelletier and Anna Tempczyk and Vincent Jacob Kalish and Kathleen D. Tucker and Richard E. Showalter and Ellen W Moomaw and Louis No{\"e}l Gastinel and Noriyuki Habuka and Xinghai Chen and Fausto C Maldonado and Jonathan Barker and Russell J. Bacquet and J Ernest Villafranca},
  journal={Nature},
  year={1995},
  volume={378},
  pages={641-644}
}

• C. Kissinger, H. Parge, +14 authors J. E. Villafranca
• Published 7 December 1995
• Chemistry, Biology
• Nature

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.