2gh5
From Proteopedia
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| - | [[Image:2gh5.gif|left|200px]] | + | [[Image:2gh5.gif|left|200px]] |
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| - | '''Crystal Structure of human Glutathione Reductase complexed with a Fluoro-Analogue of the Menadione Derivative M5''' | + | {{Structure |
| + | |PDB= 2gh5 |SIZE=350|CAPTION= <scene name='initialview01'>2gh5</scene>, resolution 1.70Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=ELI:6-(3-METHYL-1,4-DIOXO-1,4-DIHYDRONAPHTHALEN-2-YL)HEXANOIC+ACID'>ELI</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene> and <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene> | ||
| + | |ACTIVITY= [http://en.wikipedia.org/wiki/Glutathione-disulfide_reductase Glutathione-disulfide reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.8.1.7 1.8.1.7] | ||
| + | |GENE= GSR, GLUR, GRD1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | }} | ||
| + | |||
| + | '''Crystal Structure of human Glutathione Reductase complexed with a Fluoro-Analogue of the Menadione Derivative M5''' | ||
| + | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2GH5 is a [ | + | 2GH5 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GH5 OCA]. |
==Reference== | ==Reference== | ||
| - | A fluoro analogue of the menadione derivative 6-[2'-(3'-methyl)-1',4'-naphthoquinolyl]hexanoic acid is a suicide substrate of glutathione reductase. Crystal structure of the alkylated human enzyme., Bauer H, Fritz-Wolf K, Winzer A, Kuhner S, Little S, Yardley V, Vezin H, Palfey B, Schirmer RH, Davioud-Charvet E, J Am Chem Soc. 2006 Aug 23;128(33):10784-94. PMID:[http:// | + | A fluoro analogue of the menadione derivative 6-[2'-(3'-methyl)-1',4'-naphthoquinolyl]hexanoic acid is a suicide substrate of glutathione reductase. Crystal structure of the alkylated human enzyme., Bauer H, Fritz-Wolf K, Winzer A, Kuhner S, Little S, Yardley V, Vezin H, Palfey B, Schirmer RH, Davioud-Charvet E, J Am Chem Soc. 2006 Aug 23;128(33):10784-94. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16910673 16910673] |
[[Category: Glutathione-disulfide reductase]] | [[Category: Glutathione-disulfide reductase]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
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[[Category: human glutathione reductase; a fluoro-analogue of the menadione derivative m5]] | [[Category: human glutathione reductase; a fluoro-analogue of the menadione derivative m5]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 17:04:36 2008'' |
Revision as of 15:04, 20 March 2008
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| , resolution 1.70Å | |||||||
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| Ligands: | , , and | ||||||
| Gene: | GSR, GLUR, GRD1 (Homo sapiens) | ||||||
| Activity: | Glutathione-disulfide reductase, with EC number 1.8.1.7 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal Structure of human Glutathione Reductase complexed with a Fluoro-Analogue of the Menadione Derivative M5
Contents |
Overview
Glutathione reductase is an important housekeeping enzyme for redox homeostasis both in human cells and in the causative agent of tropical malaria, Plasmodium falciparum. Glutathione reductase inhibitors were shown to have anticancer and antimalarial activity per se and to contribute to the reversal of drug resistance. The development of menadione chemistry has led to the selection of 6-[2'-(3'-methyl)-1',4'-naphthoquinolyl]hexanoic acid, called M(5), as a potent reversible and uncompetitive inhibitor of both human and P. falciparum glutathione reductases. Here we describe the synthesis and kinetic characterization of a fluoromethyl-M(5) analogue that acts as a mechanism-based inhibitor of both enzymes. In the course of enzymatic catalysis, the suicide substrate is activated by one- or two-electron reduction, and then a highly reactive quinone methide is generated upon elimination of the fluorine. Accordingly the human enzyme was found to be irreversibly inactivated with a k(inact) value of 0.4 +/- 0.2 min(-1). The crystal structure of the alkylated enzyme was solved at 1.7 A resolution. It showed the inhibitor to bind covalently to the active site Cys58 and to interact noncovalently with His467', Arg347, Arg37, and Tyr114. On the basis of the crystal structure of the inactivated human enzyme and stopped-flow kinetic studies with two- and four-electron-reduced forms of the unreacted P. falciparum enzyme, a mechanism is proposed which explains naphthoquinone reduction at the flavin of glutathione reductase.
Disease
Known diseases associated with this structure: Hemolytic anemia due to glutathione reductase deficiency OMIM:[138300], Mental retardation, autosomal recessive, 6 OMIM:[138244]
About this Structure
2GH5 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
A fluoro analogue of the menadione derivative 6-[2'-(3'-methyl)-1',4'-naphthoquinolyl]hexanoic acid is a suicide substrate of glutathione reductase. Crystal structure of the alkylated human enzyme., Bauer H, Fritz-Wolf K, Winzer A, Kuhner S, Little S, Yardley V, Vezin H, Palfey B, Schirmer RH, Davioud-Charvet E, J Am Chem Soc. 2006 Aug 23;128(33):10784-94. PMID:16910673
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