title: Crystal structures of human FIH-1 in complex with quinol family inhibitors.
abstract: Hypoxia-Inducible Factor-1 (HIF-1) plays an important role as a transcription factor under hypoxia. It activates numerous genes including those involved in angiogenesis, glucose metabolisms, cell proliferation and cell survival. The HIF-1 alpha subunit is regulated by 2-oxoglutarate (OG)- and Fe(II)-dependent hydroxylases, including Factor Inhibiting HIF-1 (FIH-1). FIH-1 hydroxylates Asn803 of HIF-1 alpha and blocks its interaction with co-activating molecules. Quinol family compounds such as 5-chloro-7-iodo-8-hydroxyquinoline (Clioquinol) have been shown to inhibit the hydroxylation activity of FIH-1. Here we determined the complex crystal structures of FIH-1: Clioquinol and FIH-1: 8-Hydroxyquinoline. Clioquinol and 8-Hydroxyquinoline bind to the active site of FIH-1 by coordinating the Fe(II) ion, thereby inhibiting the binding of a co-substrate, 2OG. Contrary to other known FIH-1 inhibitors that have negative charges, Clioquinol and 8-hydroxyquinoline are neutral in charge and can provide a template for improved inhibitor design that can selectively inhibit FIH-1.
authors.affiliation: Department of Life Science, University of Seoul, Seoul 130-743, Korea.
authors.forename: Hyunjin
authors.initials: H
authors.lastname: Moon
authors.forename: Sojung
authors.initials: S
authors.lastname: Han
authors.forename: Hyunsung
authors.initials: H
authors.lastname: Park
authors.forename: Jungwoo
authors.initials: J
authors.lastname: Choe
mesh_terms: D015687:Cell Hypoxia; D007464:Clioquinol / Q000737:chemistry*; D003460:Crystallization; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D006899:Mixed Function Oxygenases; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000378:metabolism; D015125:Oxyquinoline / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007656:Ketoglutaric Acids; D046912:Multiprotein Complexes; D012097:Repressor Proteins; D015125:Oxyquinoline; D007464:Clioquinol; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human