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1aui
From Proteopedia
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==Overview== | ==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. | 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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| + | ==Disease== | ||
| + | Known diseases associated with this structure: Cornea plana congenita, recessive OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=603288 603288]], Myotonic dystrophy, type 2 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=116955 116955]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: phosphatase]] | [[Category: phosphatase]] | ||
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov | + | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 16:02:15 2007'' |
Revision as of 13:55, 12 November 2007
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HUMAN CALCINEURIN HETERODIMER
Contents |
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 Structure known Active 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
Page seeded by OCA on Mon Nov 12 16:02:15 2007
