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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
Sep 30, 2023 Vol.46 No.9, pp. 527~572
COVER PICTURE
Chronic obstructive pulmonary disease (COPD) is marked by airspace enlargement (emphysema) and small airway fibrosis, leading to airflow obstruction and eventual respiratory failure. Shown is a microphotograph of hematoxylin and eosin (H&E)-stained histological sections of the enlarged alveoli as an indicator of emphysema. Piao et al. (pp. 558-572) demonstrate that recombinant human hyaluronan and proteoglycan link protein 1 (rhHAPLN1) significantly reduces the extended airspaces of the emphysematous alveoli by increasing the levels of TGF-β receptor I and SIRT1/6, as a previously unrecognized mechanism in human alveolar epithelial cells, and consequently mitigates COPD.

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