|
|
| Line 1: |
Line 1: |
| | | | |
| | ==Crystal Structure Analysis of GSTA1-1 in complex with chlorambucil== | | ==Crystal Structure Analysis of GSTA1-1 in complex with chlorambucil== |
| - | <StructureSection load='4hj2' size='340' side='right' caption='[[4hj2]], [[Resolution|resolution]] 2.10Å' scene=''> | + | <StructureSection load='4hj2' size='340' side='right'caption='[[4hj2]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4hj2]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4HJ2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4HJ2 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4hj2]] is a 2 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=4HJ2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HJ2 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=LZ6:L-GAMMA-GLUTAMYL-S-(2-{[4-(3-CARBOXYPROPYL)PHENYL](2-CHLOROETHYL)AMINO}ETHYL)-L-CYSTEINYLGLYCINE'>LZ6</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LZ6:L-GAMMA-GLUTAMYL-S-(2-{[4-(3-CARBOXYPROPYL)PHENYL](2-CHLOROETHYL)AMINO}ETHYL)-L-CYSTEINYLGLYCINE'>LZ6</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GSTA1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4hj2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hj2 OCA], [https://pdbe.org/4hj2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hj2 RCSB], [https://www.ebi.ac.uk/pdbsum/4hj2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hj2 ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glutathione_transferase Glutathione transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.18 2.5.1.18] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4hj2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hj2 OCA], [http://pdbe.org/4hj2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4hj2 RCSB], [http://www.ebi.ac.uk/pdbsum/4hj2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4hj2 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GSTA1_HUMAN GSTA1_HUMAN]] Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.<ref>PMID:20606271</ref> | + | [https://www.uniprot.org/uniprot/GSTA1_HUMAN GSTA1_HUMAN] Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.<ref>PMID:20606271</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 22: |
Line 20: |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Glutathione S-transferase|Glutathione S-transferase]] | + | *[[Glutathione S-transferase 3D structures|Glutathione S-transferase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Glutathione transferase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Chiniadis, L]] | + | [[Category: Chiniadis L]] |
| - | [[Category: Karpusas, M]] | + | [[Category: Karpusas M]] |
| - | [[Category: Labrou, N E]] | + | [[Category: Labrou NE]] |
| - | [[Category: Alpha-beta]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
GSTA1_HUMAN Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.[1]
Publication Abstract from PubMed
Glutathione transferases (GSTs) are enzymes that contribute to cellular detoxification by catalysing the nucleophilic attack of glutathione (GSH) on the electrophilic centre of a number of xenobiotic compounds, including several chemotherapeutic drugs. In the present work we investigated the interaction of the chemotherapeutic drug chlorambucil (CBL) with human GSTA1-1 (hGSTA1-1) using kinetic analysis, protein crystallography and molecular dynamics. In the presence of GSH, CBL behaves as an efficient substrate for hGSTA1-1. The rate-limiting step of the catalytic reaction between CBL and GSH is viscosity-dependent and kinetic data suggest that product release is rate-limiting. The crystal structure of the hGSTA1-1/CBL-GSH complex was solved at 2.1 A resolution by molecular replacement. CBL is bound at the H-site attached to the thiol group of GSH, is partially ordered and exposed to the solvent, making specific interactions with the enzyme. Molecular dynamics simulations based on the crystal structure indicated high mobility of the CBL moiety and stabilization of the C-terminal helix due to the presence of the adduct. In the absence of GSH, CBL is shown to be an alkylating irreversible inhibitor for hGSTA1-1. Inactivation of the enzyme by CBL followed a biphasic pseudo-first-order saturation kinetics with approximately 1 mol of CBL per mol of dimeric enzyme being incorporated. Structural analysis suggested that the modifying residue is Cys112 which is located at the entrance of the H-site. The results are indicative of a structural communication between the subunits on the basis of mutually exclusive modification of Cys112, indicating that the two enzyme active sites are presumably coordinated.
The interaction of the chemotherapeutic drug chlorambucil with human glutathione transferase A1-1: kinetic and structural analysis.,Karpusas M, Axarli I, Chiniadis L, Papakyriakou A, Bethanis K, Scopelitou K, Clonis YD, Labrou NE PLoS One. 2013;8(2):e56337. doi: 10.1371/journal.pone.0056337. Epub 2013 Feb 27. PMID:23460799[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Achilonu I, Gildenhuys S, Fisher L, Burke J, Fanucchi S, Sewell BT, Fernandes M, Dirr HW. The role of a topologically conserved isoleucine in glutathione transferase structure, stability and function. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2010 Jul 1;66(Pt, 7):776-80. Epub 2010 Jun 23. PMID:20606271 doi:10.1107/S1744309110019135
- ↑ Karpusas M, Axarli I, Chiniadis L, Papakyriakou A, Bethanis K, Scopelitou K, Clonis YD, Labrou NE. The interaction of the chemotherapeutic drug chlorambucil with human glutathione transferase A1-1: kinetic and structural analysis. PLoS One. 2013;8(2):e56337. doi: 10.1371/journal.pone.0056337. Epub 2013 Feb 27. PMID:23460799 doi:http://dx.doi.org/10.1371/journal.pone.0056337
|
