1h2k
From Proteopedia
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==Overview== | ==Overview== | ||
| - | The activity of the transcription factor hypoxia-inducible factor (HIF) is, regulated by oxygen-dependent hydroxylation. Under normoxic conditions, hydroxylation of proline residues triggers destruction of its, alpha-subunit while hydroxylation of Asn(803) in the C-terminal, transactivation domain of HIF-1 alpha (CAD) prevents its interaction with, p300. Here we report crystal structures of the asparagine hydroxylase, (factor-inhibiting HIF, FIH) complexed with Fe((II)), 2-oxoglutarate, cosubstrate, and CAD fragments, which reveal the structural basis of HIF, modification. CAD binding to FIH occurs via an induced fit process at two, distinct interaction sites. At the hydroxylation site CAD adopts a loop, conformation, contrasting with a helical conformation for the same, residues when ... | + | The activity of the transcription factor hypoxia-inducible factor (HIF) is, regulated by oxygen-dependent hydroxylation. Under normoxic conditions, hydroxylation of proline residues triggers destruction of its, alpha-subunit while hydroxylation of Asn(803) in the C-terminal, transactivation domain of HIF-1 alpha (CAD) prevents its interaction with, p300. Here we report crystal structures of the asparagine hydroxylase, (factor-inhibiting HIF, FIH) complexed with Fe((II)), 2-oxoglutarate, cosubstrate, and CAD fragments, which reveal the structural basis of HIF, modification. CAD binding to FIH occurs via an induced fit process at two, distinct interaction sites. At the hydroxylation site CAD adopts a loop, conformation, contrasting with a helical conformation for the same, residues when bound to p300. Asn(803) of CAD is buried and precisely, orientated in the active site such that hydroxylation occurs at its, beta-carbon. Together with structures with the inhibitors Zn((II)) and, N-oxaloylglycine, analysis of the FIH-CAD complexes will assist design of, hydroxylase inhibitors with proangiogenic properties. Conserved structural, motifs within FIH imply it is one of an extended family of Fe((II)), oxygenases involved in gene regulation. |
==About this Structure== | ==About this Structure== | ||
| - | 1H2K is a | + | 1H2K is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with FE2, SO4 and OGA as [http://en.wikipedia.org/wiki/ligands ligands]. Structure known Active Site: FE1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1H2K OCA]. |
==Reference== | ==Reference== | ||
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[[Category: transcription]] | [[Category: transcription]] | ||
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 13:56:52 2007'' |
Revision as of 11:51, 5 November 2007
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FACTOR INHIBITING HIF-1 ALPHA IN COMPLEX WITH HIF-1 ALPHA FRAGMENT PEPTIDE
Overview
The activity of the transcription factor hypoxia-inducible factor (HIF) is, regulated by oxygen-dependent hydroxylation. Under normoxic conditions, hydroxylation of proline residues triggers destruction of its, alpha-subunit while hydroxylation of Asn(803) in the C-terminal, transactivation domain of HIF-1 alpha (CAD) prevents its interaction with, p300. Here we report crystal structures of the asparagine hydroxylase, (factor-inhibiting HIF, FIH) complexed with Fe((II)), 2-oxoglutarate, cosubstrate, and CAD fragments, which reveal the structural basis of HIF, modification. CAD binding to FIH occurs via an induced fit process at two, distinct interaction sites. At the hydroxylation site CAD adopts a loop, conformation, contrasting with a helical conformation for the same, residues when bound to p300. Asn(803) of CAD is buried and precisely, orientated in the active site such that hydroxylation occurs at its, beta-carbon. Together with structures with the inhibitors Zn((II)) and, N-oxaloylglycine, analysis of the FIH-CAD complexes will assist design of, hydroxylase inhibitors with proangiogenic properties. Conserved structural, motifs within FIH imply it is one of an extended family of Fe((II)), oxygenases involved in gene regulation.
About this Structure
1H2K is a Protein complex structure of sequences from Homo sapiens with FE2, SO4 and OGA as ligands. Structure known Active Site: FE1. Full crystallographic information is available from OCA.
Reference
Structure of factor-inhibiting hypoxia-inducible factor (HIF) reveals mechanism of oxidative modification of HIF-1 alpha., Elkins JM, Hewitson KS, McNeill LA, Seibel JF, Schlemminger I, Pugh CW, Ratcliffe PJ, Schofield CJ, J Biol Chem. 2003 Jan 17;278(3):1802-6. Epub 2002 Nov 21. PMID:12446723
Page seeded by OCA on Mon Nov 5 13:56:52 2007
Categories: Homo sapiens | Protein complex | Elkins, J.M. | Hewitson, K.S. | Mcneill, L.A. | Schlemminger, I. | Schofield, C.J. | Seibel, J.F. | FE2 | OGA | SO4 | 2-oxoglutarate | Asparaginyl hydroxylase | Dsbh | Fih | Hif | Hypoxia | Oxygenase | Phosphorylation | Transcription
