1grh
From Proteopedia
(New page: 200px<br /><applet load="1grh" size="450" color="white" frame="true" align="right" spinBox="true" caption="1grh, resolution 3.0Å" /> '''INHIBITION OF HUMAN G...) |
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| - | [[Image:1grh.gif|left|200px]]<br /><applet load="1grh" size=" | + | [[Image:1grh.gif|left|200px]]<br /><applet load="1grh" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1grh, resolution 3.0Å" /> | caption="1grh, resolution 3.0Å" /> | ||
'''INHIBITION OF HUMAN GLUTATHIONE REDUCTASE BY THE NITROSOUREA DRUGS 1,3-BIS(2-CHLOROETHYL)-1-NITROSOUREA AND 1-(2-CHLOROETHYL)-3-(2-HYDROXYETHYL)-1-NITROSOUREA'''<br /> | '''INHIBITION OF HUMAN GLUTATHIONE REDUCTASE BY THE NITROSOUREA DRUGS 1,3-BIS(2-CHLOROETHYL)-1-NITROSOUREA AND 1-(2-CHLOROETHYL)-3-(2-HYDROXYETHYL)-1-NITROSOUREA'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Glutathione reductase from human erythrocytes was inhibited by incubation | + | Glutathione reductase from human erythrocytes was inhibited by incubation with the drugs 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-(2-hydroxyethyl)-1-nitrosourea (HeCNU) under quasi-physiological conditions. For reference purposes, iodoacetamide was used for inactivating alkylation of the enzyme. In each case the modified glutathione reductase was crystallized and its structure determined. These analyses showed that in all experiments the enzyme had reacted at the distal sulfur, that is at the thiol of Cys-58, and virtually nowhere else in the visible structure. The electron density of the HeCNU derivative at 0.3 nm resolution is consistent with a 2-hydroxyethyl group. This alkyl moiety has recently been identified by chemical analysis [Schirmer, R. H., Schollhammer, T., Eisenbrand, G. and Krauth-Siegel, R. L. (1987) Free Radical Res. Commun. 3, 3-12]. The 0.2 nm resolution electron-density map of the BCNU-derivatized enzyme cannot be explained by a 2-hydroxyethyl group. Instead the modification appears as a carbamoyl moiety containing at least five non-hydrogen atoms. In this derivative the distal cysteine is forced into an unusual conformation. |
==About this Structure== | ==About this Structure== | ||
| - | 1GRH is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/ ] with CYS and EOH as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 1GRH is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/ ] with <scene name='pdbligand=CYS:'>CYS</scene> and <scene name='pdbligand=EOH:'>EOH</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GRH OCA]. |
==Reference== | ==Reference== | ||
Inhibition of human glutathione reductase by the nitrosourea drugs 1,3-bis(2-chloroethyl)-1-nitrosourea and 1-(2-chloroethyl)-3-(2-hydroxyethyl)-1-nitrosourea. A crystallographic analysis., Karplus PA, Krauth-Siegel RL, Schirmer RH, Schulz GE, Eur J Biochem. 1988 Jan 15;171(1-2):193-8. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=3338461 3338461] | Inhibition of human glutathione reductase by the nitrosourea drugs 1,3-bis(2-chloroethyl)-1-nitrosourea and 1-(2-chloroethyl)-3-(2-hydroxyethyl)-1-nitrosourea. A crystallographic analysis., Karplus PA, Krauth-Siegel RL, Schirmer RH, Schulz GE, Eur J Biochem. 1988 Jan 15;171(1-2):193-8. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=3338461 3338461] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
| - | [[Category: Karplus, P | + | [[Category: Karplus, P A.]] |
| - | [[Category: Schulz, G | + | [[Category: Schulz, G E.]] |
[[Category: CYS]] | [[Category: CYS]] | ||
[[Category: EOH]] | [[Category: EOH]] | ||
[[Category: oxidoreductase(flavoenzyme)]] | [[Category: oxidoreductase(flavoenzyme)]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:53:08 2008'' |
Revision as of 10:53, 21 February 2008
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INHIBITION OF HUMAN GLUTATHIONE REDUCTASE BY THE NITROSOUREA DRUGS 1,3-BIS(2-CHLOROETHYL)-1-NITROSOUREA AND 1-(2-CHLOROETHYL)-3-(2-HYDROXYETHYL)-1-NITROSOUREA
Overview
Glutathione reductase from human erythrocytes was inhibited by incubation with the drugs 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-(2-hydroxyethyl)-1-nitrosourea (HeCNU) under quasi-physiological conditions. For reference purposes, iodoacetamide was used for inactivating alkylation of the enzyme. In each case the modified glutathione reductase was crystallized and its structure determined. These analyses showed that in all experiments the enzyme had reacted at the distal sulfur, that is at the thiol of Cys-58, and virtually nowhere else in the visible structure. The electron density of the HeCNU derivative at 0.3 nm resolution is consistent with a 2-hydroxyethyl group. This alkyl moiety has recently been identified by chemical analysis [Schirmer, R. H., Schollhammer, T., Eisenbrand, G. and Krauth-Siegel, R. L. (1987) Free Radical Res. Commun. 3, 3-12]. The 0.2 nm resolution electron-density map of the BCNU-derivatized enzyme cannot be explained by a 2-hydroxyethyl group. Instead the modification appears as a carbamoyl moiety containing at least five non-hydrogen atoms. In this derivative the distal cysteine is forced into an unusual conformation.
About this Structure
1GRH is a Protein complex structure of sequences from [1] with and as ligands. Full crystallographic information is available from OCA.
Reference
Inhibition of human glutathione reductase by the nitrosourea drugs 1,3-bis(2-chloroethyl)-1-nitrosourea and 1-(2-chloroethyl)-3-(2-hydroxyethyl)-1-nitrosourea. A crystallographic analysis., Karplus PA, Krauth-Siegel RL, Schirmer RH, Schulz GE, Eur J Biochem. 1988 Jan 15;171(1-2):193-8. PMID:3338461
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