3KCX

Factor inhibiting HIF-1 alpha in complex with Clioquinol

Summary for 3KCX

• Entry DOI: 10.2210/pdb3kcx/pdb
• Related: 3KCY
• Descriptor: Hypoxia-inducible factor 1-alpha inhibitor, FE (II) ION, SULFATE ION, ... (6 entities in total)
• Functional Keywords: hypoxia, hif-1, fih-1, inhibitor, dioxygenase, iron, metal-binding, nucleus, oxidoreductase, transcription, transcription regulation
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: Q9NWT6
• Total number of polymer chains: 1
• Total formula weight: 39982.77

Authors

Moon, H.,Han, S.,Choe, J. (deposition date: 2009-10-22, release date: 2010-04-28, Last modification date: 2024-03-20)

Primary citation

Moon, H.,Han, S.,Park, H.,Choe, J.
Crystal structures of human FIH-1 in complex with quinol family inhibitors
Mol.Cells, 29:471-474, 2010

PubMed 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.

PubMed: 20396966
DOI: 10.1007/s10059-010-0058-3

Experimental method

X-RAY DIFFRACTION (2.6 Å)