Crystal structures of human FIH-1 in complex with quinol family inhibitors

Hyunjin Moon, Sojung Han, Hyunsung Park, Jungwoo Choe

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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-1α 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-1α 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.

Original languageEnglish
Pages (from-to)471-474
Number of pages4
JournalMolecules and Cells
Volume29
Issue number5
DOIs
StatePublished - May 2010

Keywords

  • clioquinol
  • crystal structure
  • factor Inhibiting HIF-1 (FIH-1)
  • hypoxia
  • hypoxia-inducible factor-1 (HIF-1)

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