6mhc

From Proteopedia

(Difference between revisions)

Current revision

Glutathione S-Transferase Omega 1 bound to covalent inhibitor 37

Structural highlights

6mhc is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2Å
Ligands:	, , ,
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 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6mhc"

Categories: Homo sapiens | Large Structures | Petrunak EM | Stuckey JA

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6mhc is ON HOLD
+==Glutathione S-Transferase Omega 1 bound to covalent inhibitor 37==
+<StructureSection load='6mhc' size='340' side='right'caption='[[6mhc]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6mhc]] 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=6MHC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6MHC FirstGlance]. <br>
+</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>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=JRM:methyl+N-(4-phenyl-1,3-thiazol-2-yl)-N-propanoylglycinate'>JRM</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></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=6mhc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mhc OCA], [https://pdbe.org/6mhc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mhc RCSB], [https://www.ebi.ac.uk/pdbsum/6mhc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mhc ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://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 ==
+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.
-Authors: Petrunak, E.M., Stuckey, J.A.
+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<ref>PMID:30735370</ref>
-Description: Glutathione S-Transferase Omega 1 bound to covalent inhibitor 37
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Petrunak, E.M]]
+<div class="pdbe-citations 6mhc" style="background-color:#fffaf0;"></div>
-[[Category: Stuckey, J.A]]
+==See Also==
+*[[Glutathione S-transferase 3D structures|Glutathione S-transferase 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Petrunak EM]]
+[[Category: Stuckey JA]]

6mhc

From Proteopedia

Current revision

Glutathione S-Transferase Omega 1 bound to covalent inhibitor 37

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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