Abstract:
: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.
journal_name
Proc Natl Acad Sci U S Aauthors
Dann CE 3rd,Bruick RK,Deisenhofer Jdoi
10.1073/pnas.202614999keywords:
subject
Has Abstractpub_date
2002-11-26 00:00:00pages
15351-6issue
24eissn
0027-8424issn
1091-6490pii
202614999journal_volume
99pub_type
杂志文章abstract::A striking feature of the human genome is the dearth of CpG dinucleotides (CpGs) interrupted occasionally by CpG islands (CGIs), regions with relatively high content of the dinucleotide. CGIs are generally associated with promoters; genes, whose promoters are especially rich in CpG sequences, tend to be expressed in m...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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abstract::Untargeted metabolomics of environmental samples routinely detects thousands of small molecules, the vast majority of which cannot be identified. Meta-mass shift chemical (MeMSChem) profiling was developed to identify mass differences between related molecules using molecular networks. This approach illuminates metabo...
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abstract::The matrix-2 (M2) protein from influenza A virus is a tetrameric, integral transmembrane (TM) protein that plays a vital role in viral replication by proton flux into the virus. The His37 tetrad is a pH sensor in the center of the M2 TM helix that activates the channel in response to the low endosomal pH. M2 consists ...
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2000-09-26 00:00:00