4yqm

From Proteopedia

(Difference between revisions)

Revision as of 09:45, 19 October 2016

Glutathione S-transferase Omega 1 bound to covalent inhibitor C1-27

Structural highlights

4yqm is a 3 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	4yqu, 4yqv
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[GSTO1_HUMAN] Exhibits glutathione-dependent thiol transferase and dehydroascorbate reductase activities. Has S-(phenacyl)glutathione reductase activity. Has also glutathione S-transferase activity. Participates in the biotransformation of inorganic arsenic and reduces monomethylarsonic acid (MMA) and dimethylarsonic acid.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

Glutathione S-transferase omega 1 (GSTO1) is an atypical GST isoform that is overexpressed in several cancers and has been implicated in drug resistance. Currently, no small-molecule drug targeting GSTO1 is under clinical development. Here we show that silencing of GSTO1 with siRNA significantly impairs cancer cell viability, validating GSTO1 as a potential new target in oncology. We report on the development and characterization of a series of chloroacetamide-containing potent GSTO1 inhibitors. Co-crystal structures of GSTO1 with our inhibitors demonstrate covalent binding to the active site cysteine. These potent GSTO1 inhibitors suppress cancer cell growth, enhance the cytotoxic effects of cisplatin and inhibit tumour growth in colon cancer models as single agent. Bru-seq-based transcription profiling unravelled novel roles for GSTO1 in cholesterol metabolism, oxidative and endoplasmic stress responses, cytoskeleton and cell migration. Our findings demonstrate the therapeutic utility of GSTO1 inhibitors as anticancer agents and identify the novel cellular pathways under GSTO1 regulation in colorectal cancer.

Mechanistic evaluation and transcriptional signature of a glutathione S-transferase omega 1 inhibitor.,Ramkumar K, Samanta S, Kyani A, Yang S, Tamura S, Ziemke E, Stuckey JA, Li S, Chinnaswamy K, Otake H, Debnath B, Yarovenko V, Sebolt-Leopold JS, Ljungman M, Neamati N Nat Commun. 2016 Oct 5;7:13084. doi: 10.1038/ncomms13084. PMID:27703239^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Board PG, Coggan M, Chelvanayagam G, Easteal S, Jermiin LS, Schulte GK, Danley DE, Hoth LR, Griffor MC, Kamath AV, Rosner MH, Chrunyk BA, Perregaux DE, Gabel CA, Geoghegan KF, Pandit J. Identification, characterization, and crystal structure of the Omega class glutathione transferases. J Biol Chem. 2000 Aug 11;275(32):24798-806. PMID:10783391 doi:10.1074/jbc.M001706200
↑ Zakharyan RA, Sampayo-Reyes A, Healy SM, Tsaprailis G, Board PG, Liebler DC, Aposhian HV. Human monomethylarsonic acid (MMA(V)) reductase is a member of the glutathione-S-transferase superfamily. Chem Res Toxicol. 2001 Aug;14(8):1051-7. PMID:11511179
↑ Board PG, Anders MW. Glutathione transferase omega 1 catalyzes the reduction of S-(phenacyl)glutathiones to acetophenones. Chem Res Toxicol. 2007 Jan;20(1):149-54. PMID:17226937 doi:10.1021/tx600305y
↑ Board PG, Coggan M, Cappello J, Zhou H, Oakley AJ, Anders MW. S-(4-Nitrophenacyl)glutathione is a specific substrate for glutathione transferase omega 1-1. Anal Biochem. 2008 Mar 1;374(1):25-30. Epub 2007 Sep 29. PMID:18028863 doi:10.1016/j.ab.2007.09.029
↑ Zhou H, Brock J, Casarotto MG, Oakley AJ, Board PG. Novel folding and stability defects cause a deficiency of human glutathione transferase omega 1. J Biol Chem. 2011 Feb 11;286(6):4271-9. Epub 2010 Nov 24. PMID:21106529 doi:10.1074/jbc.M110.197822
↑ Ramkumar K, Samanta S, Kyani A, Yang S, Tamura S, Ziemke E, Stuckey JA, Li S, Chinnaswamy K, Otake H, Debnath B, Yarovenko V, Sebolt-Leopold JS, Ljungman M, Neamati N. Mechanistic evaluation and transcriptional signature of a glutathione S-transferase omega 1 inhibitor. Nat Commun. 2016 Oct 5;7:13084. doi: 10.1038/ncomms13084. PMID:27703239 doi:http://dx.doi.org/10.1038/ncomms13084

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4yqm"

Categories: Stuckey, J A | Chloroacetamide | Covalent inhibitor | Thioltransferase | Transferase-transferase inhibitor complex

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 4yqm is ON HOLD  until Paper Publication
+==Glutathione S-transferase Omega 1 bound to covalent inhibitor C1-27==
+<StructureSection load='4yqm' size='340' side='right' caption='[[4yqm]], [[Resolution|resolution]] 2.38&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4yqm]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YQM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4YQM FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4G9:2-CHLORO-N-[4-CHLORO-3-(DIMETHYLSULFAMOYL)PHENYL]ACETAMIDE'>4G9</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene></td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4yqu|4yqu]], [[4yqv|4yqv]]</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=4yqm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yqm OCA], [http://pdbe.org/4yqm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4yqm RCSB], [http://www.ebi.ac.uk/pdbsum/4yqm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4yqm ProSAT]</span></td></tr>
+</table>
+== Function ==
+[[http://www.uniprot.org/uniprot/GSTO1_HUMAN GSTO1_HUMAN]] Exhibits glutathione-dependent thiol transferase and dehydroascorbate reductase activities. Has S-(phenacyl)glutathione reductase activity. Has also glutathione S-transferase activity. Participates in the biotransformation of inorganic arsenic and reduces monomethylarsonic acid (MMA) and dimethylarsonic acid.<ref>PMID:10783391</ref> <ref>PMID:11511179</ref> <ref>PMID:17226937</ref> <ref>PMID:18028863</ref> <ref>PMID:21106529</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Glutathione S-transferase omega 1 (GSTO1) is an atypical GST isoform that is overexpressed in several cancers and has been implicated in drug resistance. Currently, no small-molecule drug targeting GSTO1 is under clinical development. Here we show that silencing of GSTO1 with siRNA significantly impairs cancer cell viability, validating GSTO1 as a potential new target in oncology. We report on the development and characterization of a series of chloroacetamide-containing potent GSTO1 inhibitors. Co-crystal structures of GSTO1 with our inhibitors demonstrate covalent binding to the active site cysteine. These potent GSTO1 inhibitors suppress cancer cell growth, enhance the cytotoxic effects of cisplatin and inhibit tumour growth in colon cancer models as single agent. Bru-seq-based transcription profiling unravelled novel roles for GSTO1 in cholesterol metabolism, oxidative and endoplasmic stress responses, cytoskeleton and cell migration. Our findings demonstrate the therapeutic utility of GSTO1 inhibitors as anticancer agents and identify the novel cellular pathways under GSTO1 regulation in colorectal cancer.
-Authors: Stuckey, J.A.
+Mechanistic evaluation and transcriptional signature of a glutathione S-transferase omega 1 inhibitor.,Ramkumar K, Samanta S, Kyani A, Yang S, Tamura S, Ziemke E, Stuckey JA, Li S, Chinnaswamy K, Otake H, Debnath B, Yarovenko V, Sebolt-Leopold JS, Ljungman M, Neamati N Nat Commun. 2016 Oct 5;7:13084. doi: 10.1038/ncomms13084. PMID:27703239<ref>PMID:27703239</ref>
-Description: Glutathione S-transferase Omega 1 bound to covalent inhibitor C1-27
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Stuckey, J.A]]
+<div class="pdbe-citations 4yqm" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Stuckey, J A]]
+[[Category: Chloroacetamide]]
+[[Category: Covalent inhibitor]]
+[[Category: Thioltransferase]]
+[[Category: Transferase-transferase inhibitor complex]]

4yqm

From Proteopedia

Revision as of 09:45, 19 October 2016

Glutathione S-transferase Omega 1 bound to covalent inhibitor C1-27

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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