1mze: Difference between revisions
New page: left|200px<br /> <applet load="1mze" size="450" color="white" frame="true" align="right" spinBox="true" caption="1mze, resolution 2.20Å" /> '''Human Factor Inhibi... |
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[[Image:1mze.gif|left|200px]]<br /> | [[Image:1mze.gif|left|200px]]<br /><applet load="1mze" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="1mze, resolution 2.20Å" /> | caption="1mze, resolution 2.20Å" /> | ||
'''Human Factor Inhibiting HIF (FIH1)'''<br /> | '''Human Factor Inhibiting HIF (FIH1)'''<br /> | ||
==Overview== | ==Overview== | ||
Precise regulation of the evolutionarily conserved hypoxia-inducible | Precise regulation of the evolutionarily conserved hypoxia-inducible transcription factor (HIF) ensures proper adaptation to variations in oxygen availability throughout development and into adulthood. Oxygen-dependent regulation of HIF stability and activity are mediated by hydroxylation of conserved proline and asparagine residues, respectively. Because the relevant prolyl and asparginyl hydroxylases use O(2) to effect these posttranslational modifications, these enzymes are implicated as direct oxygen sensors in the mammalian hypoxic response pathway. Here we present the structure of factor-inhibiting HIF-1 (FIH-1), the pertinent asparaginyl hydroxylase involved in hypoxic signaling. Hydroxylation of the C-terminal transactivation domain (CTAD) of HIF by FIH-1 prevents CTAD association with transcriptional coactivators under normoxic conditions. Consistent with other structurally known hydroxylases, FIH-1 is comprised of a beta-strand jellyroll core with both Fe(II) and the cosubstrate 2-oxoglutarate bound in the active site. Details of the molecular contacts at the active site of FIH-1 have been elucidated and provide a platform for future drug design. Furthermore, the structure reveals the presence of a FIH-1 homodimer that forms in solution and is essential for FIH activity. | ||
==About this Structure== | ==About this Structure== | ||
1MZE is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with TAR and FE2 as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | 1MZE is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=TAR:'>TAR</scene> and <scene name='pdbligand=FE2:'>FE2</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1MZE OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Bruick, R | [[Category: Bruick, R K.]] | ||
[[Category: Deisenhofer, J.]] | [[Category: Deisenhofer, J.]] | ||
[[Category: III, C | [[Category: III, C E.Dann.]] | ||
[[Category: FE2]] | [[Category: FE2]] | ||
[[Category: TAR]] | [[Category: TAR]] | ||
[[Category: beta-jellyroll]] | [[Category: beta-jellyroll]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:00:35 2008'' | ||
Revision as of 15:00, 21 February 2008
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Human Factor Inhibiting HIF (FIH1)
OverviewOverview
Precise regulation of the evolutionarily conserved hypoxia-inducible transcription factor (HIF) ensures proper adaptation to variations in oxygen availability throughout development and into adulthood. Oxygen-dependent regulation of HIF stability and activity are mediated by hydroxylation of conserved proline and asparagine residues, respectively. Because the relevant prolyl and asparginyl hydroxylases use O(2) to effect these posttranslational modifications, these enzymes are implicated as direct oxygen sensors in the mammalian hypoxic response pathway. Here we present the structure of factor-inhibiting HIF-1 (FIH-1), the pertinent asparaginyl hydroxylase involved in hypoxic signaling. Hydroxylation of the C-terminal transactivation domain (CTAD) of HIF by FIH-1 prevents CTAD association with transcriptional coactivators under normoxic conditions. Consistent with other structurally known hydroxylases, FIH-1 is comprised of a beta-strand jellyroll core with both Fe(II) and the cosubstrate 2-oxoglutarate bound in the active site. Details of the molecular contacts at the active site of FIH-1 have been elucidated and provide a platform for future drug design. Furthermore, the structure reveals the presence of a FIH-1 homodimer that forms in solution and is essential for FIH activity.
About this StructureAbout this Structure
1MZE is a Single protein structure of sequence from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Structure of factor-inhibiting hypoxia-inducible factor 1: An asparaginyl hydroxylase involved in the hypoxic response pathway., Dann CE 3rd, Bruick RK, Deisenhofer J, Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15351-6. Epub 2002 Nov 13. PMID:12432100
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