1IZ3

Dimeric structure of FIH (Factor inhibiting HIF)

Summary for 1IZ3

• Entry DOI: 10.2210/pdb1iz3/pdb
• Descriptor: FIH, SULFATE ION (2 entities in total)
• Functional Keywords: double beta-sheet helix, transcription
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus (Potential): Q9NWT6
• Total number of polymer chains: 1
• Total formula weight: 40729.38

Authors

Lee, C.,Kim, S.-J.,Jeong, D.-G.,Lee, S.M.,Ryu, S.-E. (deposition date: 2002-09-19, release date: 2003-06-10, Last modification date: 2024-10-30)

Primary citation

Lee, C.,Kim, S.J.,Jeong, D.G.,Lee, S.M.,Ryu, S.E.
Structure of human FIH-1 reveals a unique active site pocket and interaction sites for HIF-1 and von Hippel-Lindau.
J.Biol.Chem., 278:7558-7563, 2003

PubMed Abstract: The master switch of cellular hypoxia responses, hypoxia-inducible factor 1 (HIF-1), is hydroxylated by factor inhibiting HIF-1 (FIH-1) at a conserved asparagine residue under normoxia, which suppresses transcriptional activity of HIF-1 by abrogating its interaction with transcription coactivators. Here we report the crystal structure of human FIH-1 at 2.8-A resolution. The structural core of FIH-1 consists of a jellyroll-like beta-barrel containing the conserved ferrous-binding triad residues, confirming that FIH-1 is a member of the 2-oxoglutarate-dependent dioxygenase family. Except for the core structure and triad residues, FIH-1 has many structural deviations from other family members including N- and C-terminal insertions and various deletions in the middle of the structure. The ferrous-binding triad region is highly exposed to the solvent, which is connected to a prominent groove that may bind to a helix near the hydroxylation site of HIF-1. The structure, which is in a dimeric state, also reveals the putative von Hippel-Lindau-binding site that is distinctive to the putative HIF-1-binding site, supporting the formation of the ternary complex by FIH-1, HIF-1, and von Hippel-Lindau. The unique environment of the active site and cofactor-binding region revealed in the structure should allow design of selective drugs that can be used in ischemic diseases to promote hypoxia responses.

PubMed: 12482756
DOI: 10.1074/jbc.M210385200

Experimental method

X-RAY DIFFRACTION (2.8 Å)