1H2K

Factor Inhibiting HIF-1 alpha in complex with HIF-1 alpha fragment peptide

1H2K の概要

• エントリーDOI: 10.2210/pdb1h2k/pdb
• 関連するPDBエントリー: 1D7G 1H2L 1H2M 1H2N 1L8C 1LM8 1LQB
• 分子名称: FACTOR INHIBITING HIF1, HYPOXIA-INDUCIBLE FACTOR 1 ALPHA, FE (II) ION, ... (6 entities in total)
• 機能のキーワード: transcription activator-inhibitor complex, fih, hif, dsbh, oxygenase, transcription, hypoxia, 2- oxoglutarate, asparaginyl hydroxylase, phosphorylation, transcription activator/inhibitor
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• 細胞内の位置: Cytoplasm : Q16665
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 45230.28

構造登録者

Elkins, J.M.,Hewitson, K.S.,McNeill, L.A.,Schlemminger, I.,Seibel, J.F.,Schofield, C.J. (登録日: 2002-08-12, 公開日: 2002-11-28, 最終更新日: 2024-05-08)

主引用文献

Elkins, J.M.,Hewitson, K.S.,McNeill, L.A.,Seibel, J.F.,Schlemminger, I.,Pugh, C.,Ratcliffe, P.,Schofield, C.J.
Structure of Factor-Inhibiting Hypoxia-Inducible Factor (Hif) Reveals Mechanism of Oxidative Modification of Hif-1Alpha
J.Biol.Chem., 278:1802-1806, 2003

PubMed Abstract: 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.

PubMed: 12446723
DOI: 10.1074/JBC.C200644200

実験手法

X-RAY DIFFRACTION (2.15 Å)