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6mhb

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Revision as of 07:56, 10 April 2019

Glutathione S-Transferase Omega 1 bound to covalent inhibitor 18

Structural highlights

6mhb is a 6 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Gene:	GSTO1, GSTTLP28 (HUMAN)
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

Using reported glutathione S-transferase omega 1 (GSTO1-1) co-crystal structures, we designed and synthesized acrylamide-containing compounds that covalently bind to Cys32 on the catalytic site. Starting from a thiazole derivative 10 (GSTO1-1 IC50 = 0.6 microM), compound 18 was synthesized and co-crystalized with GSTO1. Modification on the amide moiety of hit compound 10 significantly increased the GSTO1-1 inhibitory potency. We solved the co-crystal structures of new derivatives, 37 and 44, bearing amide side chain bound to GSTO1. These new structures showed a reorientation of the phenyl thiazole core of inhibitors, 37 and 44, when compared to 18. Guided by the co-crystal structure of GSTO1:44, analog 49 was designed resulting in the most potent GSTO1-1 inhibitor (IC50 = 0.22 +/- 0.02 nM) known to date. We believe that our data will inform the future studies of developing GSTO1-1 as a new drug target for cancer therapy.

Structure-based Design of N-(5-phenylthiazol-2-yl)acrylamides as Novel and Potent Glutathione S-Transferase Omega 1 Inhibitors.,Dai W, Samanta S, Xue D, Petrunak EM, Stuckey JA, Han Y, Sun D, Wu Y, Neamati N J Med Chem. 2019 Feb 8. doi: 10.1021/acs.jmedchem.8b01960. PMID:30735370^[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
↑ Dai W, Samanta S, Xue D, Petrunak EM, Stuckey JA, Han Y, Sun D, Wu Y, Neamati N. Structure-based Design of N-(5-phenylthiazol-2-yl)acrylamides as Novel and Potent Glutathione S-Transferase Omega 1 Inhibitors. J Med Chem. 2019 Feb 8. doi: 10.1021/acs.jmedchem.8b01960. PMID:30735370 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b01960

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/6mhb"

@@ Line 1: / Line 1: @@
 ==Glutathione S-Transferase Omega 1 bound to covalent inhibitor 18==
-<StructureSection load='6mhb' size='340' side='right' caption='[[6mhb]], [[Resolution|resolution]] 2.75&Aring;' scene=''>
+<StructureSection load='6mhb' size='340' side='right'caption='[[6mhb]], [[Resolution|resolution]] 2.75&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6mhb]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MHB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MHB FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6mhb]] is a 6 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=6MHB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MHB FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=JR7:N-[4-(4-chlorophenyl)-1,3-thiazol-2-yl]propanamide'>JR7</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GSTO1, GSTTLP28 ([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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6mhb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mhb OCA], [http://pdbe.org/6mhb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mhb RCSB], [http://www.ebi.ac.uk/pdbsum/6mhb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mhb ProSAT]</span></td></tr>
 </table>
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Petrunak, E M]]
 [[Category: Stuckey, J A]]

6mhb

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Revision as of 07:56, 10 April 2019

Glutathione S-Transferase Omega 1 bound to covalent inhibitor 18

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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