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Title
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Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex.
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Authors
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C.R.Kissinger,
H.E.Parge,
D.R.Knighton,
C.T.Lewis,
L.A.Pelletier,
A.Tempczyk,
V.J.Kalish,
K.D.Tucker,
R.E.Showalter,
E.W.Moomaw.
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Ref.
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Nature, 1995,
378,
641-644.
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PubMed id
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Abstract
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Calcineurin (CaN) is a calcium- and calmodulin-dependent protein
serine/threonine phosphate which is critical for several important cellular
processes, including T-cell activation. 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). We report here the crystal structures of full-length human CaN at
2.1 A resolution and of the complex of human CaN with FKBP12-FK506 at 3.5 A
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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