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Mol. Cells 2010; 29(5): 471-474

Published online April 12, 2010

https://doi.org/10.1007/s10059-010-0058-3

© The Korean Society for Molecular and Cellular Biology

Crystal Structures of Human FIH-1 in Complex with Quinol Family Inhibitors

Hyunjin Moon, Sojung Han, Hyunsung Park, and Jungwoo Choe*

Department of Life Science, University of Seoul, Seoul 130-743, Korea

Correspondence to : *Correspondence: jchoe@uos.ac.kr

Received: November 10, 2010; Revised: January 14, 2010; Accepted: February 10, 2010

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-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.

Keywords , crystal structure, factor Inhibiting HIF-1 (FIH-1), hypoxia, hypoxia-inducible factor-1 (HIF-1)

Article

Research Article

Mol. Cells 2010; 29(5): 471-474

Published online May 31, 2010 https://doi.org/10.1007/s10059-010-0058-3

Copyright © The Korean Society for Molecular and Cellular Biology.

Crystal Structures of Human FIH-1 in Complex with Quinol Family Inhibitors

Hyunjin Moon, Sojung Han, Hyunsung Park, and Jungwoo Choe*

Department of Life Science, University of Seoul, Seoul 130-743, Korea

Correspondence to:*Correspondence: jchoe@uos.ac.kr

Received: November 10, 2010; Revised: January 14, 2010; Accepted: February 10, 2010

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-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.

Keywords: , crystal structure, factor Inhibiting HIF-1 (FIH-1), hypoxia, hypoxia-inducible factor-1 (HIF-1)

Mol. Cells
Feb 28, 2023 Vol.46 No.2, pp. 69~129
COVER PICTURE
The bulk tissue is a heterogeneous mixture of various cell types, which is depicted as a skein of intertwined threads with diverse colors each of which represents a unique cell type. Single-cell omics analysis untangles efficiently the skein according to the color by providing information of molecules at individual cells and interpretation of such information based on different cell types. The molecules that can be profiled at the individual cell by single-cell omics analysis includes DNA (bottom middle), RNA (bottom right), and protein (bottom left). This special issue reviews single-cell technologies and computational methods that have been developed for the single-cell omics analysis and how they have been applied to improve our understanding of the underlying mechanisms of biological and pathological phenomena at the single-cell level.

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