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| | <StructureSection load='5j41' size='340' side='right'caption='[[5j41]], [[Resolution|resolution]] 1.19Å' scene=''> | | <StructureSection load='5j41' size='340' side='right'caption='[[5j41]], [[Resolution|resolution]] 1.19Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5j41]] 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=5J41 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5J41 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5j41]] 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=5J41 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5J41 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3LF:3-(3,4,5-TRIMETHOXYPHENYL)PROPANOIC+ACID'>3LF</scene>, <scene name='pdbligand=GSH:GLUTATHIONE'>GSH</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.1903535Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GSTP1, FAEES3, GST3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3LF:3-(3,4,5-TRIMETHOXYPHENYL)PROPANOIC+ACID'>3LF</scene>, <scene name='pdbligand=GSH:GLUTATHIONE'>GSH</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=5j41 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j41 OCA], [https://pdbe.org/5j41 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5j41 RCSB], [https://www.ebi.ac.uk/pdbsum/5j41 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5j41 ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5j41 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j41 OCA], [http://pdbe.org/5j41 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j41 RCSB], [http://www.ebi.ac.uk/pdbsum/5j41 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j41 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GSTP1_HUMAN GSTP1_HUMAN]] Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Regulates negatively CDK5 activity via p25/p35 translocation to prevent neurodegeneration.<ref>PMID:21668448</ref> | + | [https://www.uniprot.org/uniprot/GSTP1_HUMAN GSTP1_HUMAN] Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Regulates negatively CDK5 activity via p25/p35 translocation to prevent neurodegeneration.<ref>PMID:21668448</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Glutathione transferase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Ficarro, S]] | + | [[Category: Ficarro S]] |
| - | [[Category: Gondi, S]] | + | [[Category: Gondi S]] |
| - | [[Category: Gurbani, D]] | + | [[Category: Gurbani D]] |
| - | [[Category: Harshbarger, W]] | + | [[Category: Harshbarger W]] |
| - | [[Category: Hunter, J]] | + | [[Category: Hunter J]] |
| - | [[Category: Marto, J]] | + | [[Category: Marto J]] |
| - | [[Category: Udayakumar, D]] | + | [[Category: Udayakumar D]] |
| - | [[Category: Westover, K]] | + | [[Category: Westover K]] |
| - | [[Category: Glutathione]]
| + | |
| - | [[Category: Gstp1]]
| + | |
| - | [[Category: Piperlongumine]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Function
GSTP1_HUMAN Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Regulates negatively CDK5 activity via p25/p35 translocation to prevent neurodegeneration.[1]
Publication Abstract from PubMed
Glutathione S-transferase pi 1 (GSTP1), is frequently overexpressed in cancerous tumors and is a putative target of the plant compound piperlongumine (PL), which contains two reactive olefins and inhibits proliferation in cancer cells but not normal cells. PL exposure of cancer cells results in increased reactive oxygen species and decreased glutathione (GSH). This data in tandem with other information led to the conclusion that PL inhibits GSTP1, which forms covalent bonds between GSH and various electrophilic compounds, through covalent adduct formation at PLs C7-C8 olefin, while PLs C2-C3 olefin was postulated to react with GSH. However, direct evidence for this mechanism has been lacking. To investigate, we solved the x-ray crystal structure of GSTP1 bound to PL and GSH at 1.1 Angstrom resolution to rationalize previously reported structure activity relationship studies. Surprisingly, the structure showed a hydrolysis product of PL (hPL) was conjugated to glutathione at the C7-C8 olefin, and this complex was bound to the active site of GSTP1; No covalent bond formation between hPL and GSTP1 was observed. Mass spectrometric (MS) analysis of reactions between PL and GSTP1 confirmed that PL does not label GSTP1. Moreover, MS data also indicated that nucleophilic attack on PL at the C2-C3 olefin led to PL hydrolysis. Although hPL inhibits GSTP1 enzymatic activity in vitro, treatment of cells susceptible to PL with hPL did not have significant anti-proliferative effects, suggesting hPL is not membrane permeable. Altogether, our data suggest a model wherein PL is a prodrug whose intracellular hydrolysis initiates the formation of the hPL:GSH conjugate, which blocks the active site of and inhibits GSTP1 and thereby cancer cell proliferation.
Structural and Biochemical Analyses Reveal the Mechanism of Glutathione S-Transferase Pi 1 Inhibition by the Anti-cancer Compound Piperlongumine.,Harshbarger W, Gondi S, Ficarro SB, Hunter J, Udayakumar D, Gurbani D, Singer W, Liu Y, Li L, Marto JA, Westover KD J Biol Chem. 2016 Nov 21. pii: jbc.M116.750299. PMID:27872191[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Sun KH, Chang KH, Clawson S, Ghosh S, Mirzaei H, Regnier F, Shah K. Glutathione-S-transferase P1 is a critical regulator of Cdk5 kinase activity. J Neurochem. 2011 Sep;118(5):902-14. doi: 10.1111/j.1471-4159.2011.07343.x. Epub , 2011 Jul 8. PMID:21668448 doi:10.1111/j.1471-4159.2011.07343.x
- ↑ Harshbarger W, Gondi S, Ficarro SB, Hunter J, Udayakumar D, Gurbani D, Singer W, Liu Y, Li L, Marto JA, Westover KD. Structural and Biochemical Analyses Reveal the Mechanism of Glutathione S-Transferase Pi 1 Inhibition by the Anti-cancer Compound Piperlongumine. J Biol Chem. 2016 Nov 21. pii: jbc.M116.750299. PMID:27872191 doi:http://dx.doi.org/10.1074/jbc.M116.750299
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