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| | {{STRUCTURE_1xan| PDB=1xan | SCENE= }} | | {{STRUCTURE_1xan| PDB=1xan | SCENE= }} |
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| - | '''HUMAN GLUTATHIONE REDUCTASE IN COMPLEX WITH A XANTHENE INHIBITOR'''
| + | ===HUMAN GLUTATHIONE REDUCTASE IN COMPLEX WITH A XANTHENE INHIBITOR=== |
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| - | ==Overview==
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| - | We have determined the crystal structure of a complex between the noncompetitive inhibitor (Kis = 27 microM, Kii = 48 microM with respect to oxidized glutathione (GSSG) and Kis = 144 microM, Kii = 176 microM with respect to NADPH) 6-hydroxy-3-oxo-3H-xanthene-9-propionic acid (XAN) and human glutathione reductase (hGR). The structure, refined to an R-factor of 0.158 at 2.0 A resolution, reveals XAN bound in the large cavity present at the hGR dimer interface where it does not overlap the glutathione binding site. The inhibitor binding causes extensive local structural changes that primarily involve amino acid residues from a 30-residue alpha-helix that lines the cavity and contributes to the active site of hGR. Despite the lack of physical overlap of XAN with the GSSG binding site, no GSSG binding is seen in soaks carried out with high XAN and GSSG concentrations, suggesting that some subtle interaction between the sites exists. An earlier crystallographic analysis on the complex between hGR and 3,7-diamino-2,8-dimethyl-5-phenyl-phenazinium chloride (safranin) showed that safranin bound at this same site. We have found that safranin also inhibits hGR in a noncompetitive fashion, but it binds about 16 times less tightly (Kis = 453 microM, Kii = 586 microM with respect to GSSG) than XAN and does not preclude the binding of GSSG in the crystal. Although in structure-based drug design competitive inhibitors are usually targetted, XAN's binding to a well defined site that is unique to glutathione reductase suggests that noncompetitive inhibitors could also serve as lead compounds for structure-based drug design, in particular as components of chimeric inhibitors.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_8626496}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 8626496 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_8626496}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Glutathione reducatase]] | | [[Category: Glutathione reducatase]] |
| | [[Category: Oxidoreductase]] | | [[Category: Oxidoreductase]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 14:47:21 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 17:47:51 2008'' |
Revision as of 14:47, 28 July 2008
Template:STRUCTURE 1xan
HUMAN GLUTATHIONE REDUCTASE IN COMPLEX WITH A XANTHENE INHIBITOR
Template:ABSTRACT PUBMED 8626496
About this Structure
1XAN is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Kinetics and crystallographic analysis of human glutathione reductase in complex with a xanthene inhibitor., Savvides SN, Karplus PA, J Biol Chem. 1996 Apr 5;271(14):8101-7. PMID:8626496
Page seeded by OCA on Mon Jul 28 17:47:51 2008
