Structural basis for binding of cyclic 2-oxoglutarate analogues to factor-inhibiting hypoxia-inducible factor

被引：22

作者：

Conejo-Garcia, Ana ^{[1
]}

McDonough, Michael A. ^{[1
]}

Loenarz, Christoph ^{[1
]}

McNeill, Luke A. ^{[1
]}

Hewitson, Kirsty S. ^{[1
]}

Ge, Wei ^{[1
]}

Lienard, Benoit M. ^{[1
]}

Schofield, Christopher J. ^{[1
]}

Clifton, Ian J. ^{[1
]}

机构：

[1] Univ Oxford, Dept Chem, Chem Res Lab, Oxford OX1 3TA, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 20期

基金：

英国生物技术与生命科学研究理事会; 英国惠康基金;

关键词：

Factor inhibiting hypoxia-inducible factor; Oxygenase; Hypoxic response; Hydroxamic acid; 2-Oxoglutarate analogue; PROLYL HYDROXYLASE;

D O I：

10.1016/j.bmcl.2010.08.032

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Aromatic analogues of the 2-oxoglutarate co-substrate of the hypoxia-inducible factor hydroxylases are shown to bind at the active site iron: Pyridine-2,4-dicarboxylate binds as anticipated with a single molecule chelating the iron in a bidentate manner. The binding mode of a hydroxamic acid analogue, at least in the crystalline state, is unusual because two molecules of the inhibitor are observed at the active site and partial displacement of the iron binding aspartyl residue was observed. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：6125 / 6128

页数：4

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