1xan

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[[Image:1xan.jpg|left|200px]]<br /><applet load="1xan" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1xan, resolution 2.0&Aring;" />
 
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'''HUMAN GLUTATHIONE REDUCTASE IN COMPLEX WITH A XANTHENE INHIBITOR'''<br />
 
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==Overview==
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==HUMAN GLUTATHIONE REDUCTASE IN COMPLEX WITH A XANTHENE INHIBITOR==
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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.
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<StructureSection load='1xan' size='340' side='right'caption='[[1xan]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1xan]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XAN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1XAN FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=HXP:3,6-DIHYDROXY-XANTHENE-9-PROPIONIC+ACID'>HXP</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1xan FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xan OCA], [https://pdbe.org/1xan PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1xan RCSB], [https://www.ebi.ac.uk/pdbsum/1xan PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1xan ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/GSHR_HUMAN GSHR_HUMAN] Maintains high levels of reduced glutathione in the cytosol.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/xa/1xan_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1xan ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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==Disease==
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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<ref>PMID:8626496</ref>
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Known diseases associated with this structure: Hemolytic anemia due to glutathione reductase deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=138300 138300]], Mental retardation, autosomal recessive, 6 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=138244 138244]]
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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1XAN is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=FAD:'>FAD</scene> and <scene name='pdbligand=HXP:'>HXP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XAN OCA].
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</div>
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<div class="pdbe-citations 1xan" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=8626496 8626496]
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*[[Glutathione Reductase|Glutathione Reductase]]
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[[Category: Glutathione-disulfide reductase]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Karplus, P.A.]]
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[[Category: Karplus PA]]
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[[Category: Savvides, S.N.]]
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[[Category: Savvides SN]]
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[[Category: FAD]]
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[[Category: HXP]]
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[[Category: flavoenzyme]]
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[[Category: glutathione reducatase]]
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[[Category: oxidoreductase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 17:08:37 2008''
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HUMAN GLUTATHIONE REDUCTASE IN COMPLEX WITH A XANTHENE INHIBITOR

PDB ID 1xan

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