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

Published online May 31, 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
Jul 31, 2022 Vol.45 No.7, pp. 435~512
COVER PICTURE
Mesenchymal stem cells (MSCs) are multipotent stem cells capable of differentiating into mesodermal lineages like adipogenic, osteogenic, and chondrogenic. Alcian blue-positive extracellular matrix secreted by chondrocytes in the lacuna confirmed the chondrogenic differentiation of MSCs (Bashyal et al., pp. 479-494).

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