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KMID : 0578320100290050471
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Molecules and Cells
2010 Volume.29 No. 5 p.471 ~ p.474
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Crystal Structures of Human FIH-1 in Complex with Quinol Family Inhibitors
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Moon Hyun-Jin
Han So-Jung
Park Hyun-Sung
Choe Jung-Woo
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Abstract
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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-hydroxyqui-noline (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-Hydro-xyquinoline. 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.
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KEYWORD
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crystal structure, factor Inhibiting HIF-1 (FIH-1), hypoxia, hypoxia-inducible factor-1 (HIF-1)
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