1aui: Difference between revisions
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==Overview== | ==Overview== | ||
Calcineurin (CaN) is a calcium- and calmodulin-dependent protein | 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. | ||
==Disease== | ==Disease== | ||
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[[Category: Phosphoprotein phosphatase]] | [[Category: Phosphoprotein phosphatase]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Kissinger, C | [[Category: Kissinger, C R.]] | ||
[[Category: Knighton, D | [[Category: Knighton, D R.]] | ||
[[Category: Lewis, C | [[Category: Lewis, C T.]] | ||
[[Category: Parge, H | [[Category: Parge, H E.]] | ||
[[Category: Pelletier, L | [[Category: Pelletier, L A.]] | ||
[[Category: Tempczyk, A.]] | [[Category: Tempczyk, A.]] | ||
[[Category: Villafranca, J | [[Category: Villafranca, J E.]] | ||
[[Category: CA]] | [[Category: CA]] | ||
[[Category: FE]] | [[Category: FE]] | ||
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[[Category: phosphatase]] | [[Category: phosphatase]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 11:48:25 2008'' | ||
Revision as of 09:48, 21 February 2008
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HUMAN CALCINEURIN HETERODIMER
Overview
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.
Disease
Known diseases associated with this structure: Cornea plana congenita, recessive OMIM:[603288], Myotonic dystrophy, type 2 OMIM:[116955]
About this Structure
1AUI is a Protein complex structure of sequences from Homo sapiens with CA, ZN and FE as ligands. Active as Phosphoprotein phosphatase, with EC number 3.1.3.16 Known structural/functional Sites: CA1, CA2, CA3, CA4, FEB and ZNB. Full crystallographic information is available from OCA.
Reference
Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex., Kissinger CR, Parge HE, Knighton DR, Lewis CT, Pelletier LA, Tempczyk A, Kalish VJ, Tucker KD, Showalter RE, Moomaw EW, et al., Nature. 1995 Dec 7;378(6557):641-4. PMID:8524402
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