3gur

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Revision as of 07:13, 1 November 2017

Crystal Structure of mu class glutathione S-transferase (GSTM2-2) in complex with glutathione and 6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX)

Structural highlights

3gur is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	3gus
Activity:	Glutathione transferase, with EC number 2.5.1.18
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[GSTM2_HUMAN] Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.^[1]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Glutathione S-transferases (GST) constitute a superfamily of enzymes with diversified functions including detoxification from xenobiotics. In many human cancers, Pi class GST (GSTP1-1) is overexpressed and contributes to multidrug resistance by conjugating chemotherapeutics. In addition, GSTP1-1 displays antiapoptotic activity by interacting with c-Jun NH(2)-terminal kinase, a key regulator of apoptosis. Therefore, GSTP1-1 is considered a promising target for pharmaceutical treatment. Recently, a potent inhibitor of GSTs, 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX), was identified and tested on several tumor cell lines demonstrating high antiproliferative activity. To establish the structural basis of NBDHEX activity, we determined the crystal structure of NBDHEX bound to either GSTP1-1 or GSTM2-2 (mu class). NBDHEX in both cases binds to the H-site but occupies different positions. Furthermore, the compound is covalently attached to the GSH sulfur in the GSTM2-2 crystal, forming a sigma-complex, although it is bound but not conjugated in the GSTP1-1 crystal. Several differences in the H-sites of the two isozymes determine the higher affinity of NBDHEX for GSTM2-2 with respect to GSTP1-1. One such difference is the presence of Ile(104) in GSTP1-1 close to the bound NBDHEX, whereas the corresponding position is occupied by an alanine in GSTM2-2. Mutation of Ile(104) into valine is a frequent GSTP1-1 polymorphism and we show here that the Ile(104)Val and Ile(104)Ala variants display a 4-fold higher affinity for the compound. Remarkably, the GSTP1-1/Ile(104)Ala structure in complex with NBDHEX shows a considerable shift of the compound inside the H-site. These data might be useful for the development of new anticancer compounds.

Structural basis for the binding of the anticancer compound 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol to human glutathione s-transferases.,Federici L, Lo Sterzo C, Pezzola S, Di Matteo A, Scaloni F, Federici G, Caccuri AM Cancer Res. 2009 Oct 15;69(20):8025-34. Epub 2009 Oct 6. PMID:19808963^[2]

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

References

↑ Norrgard MA, Ivarsson Y, Tars K, Mannervik B. Alternative mutations of a positively selected residue elicit gain or loss of functionalities in enzyme evolution. Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):4876-81. Epub 2006 Mar 20. PMID:16549767
↑ Federici L, Lo Sterzo C, Pezzola S, Di Matteo A, Scaloni F, Federici G, Caccuri AM. Structural basis for the binding of the anticancer compound 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol to human glutathione s-transferases. Cancer Res. 2009 Oct 15;69(20):8025-34. Epub 2009 Oct 6. PMID:19808963 doi:10.1158/0008-5472.CAN-09-1314

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3gur"

@@ Line 1: / Line 1: @@
 ==Crystal Structure of mu class glutathione S-transferase (GSTM2-2) in complex with glutathione and 6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX)==
 <StructureSection load='3gur' size='340' side='right' caption='[[3gur]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3gus|3gus]]</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=3gur FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3gur OCA], [http://pdbe.org/3gur PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3gur RCSB], [http://www.ebi.ac.uk/pdbsum/3gur PDBsum]</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=3gur FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3gur OCA], [http://pdbe.org/3gur PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3gur RCSB], [http://www.ebi.ac.uk/pdbsum/3gur PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3gur ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 29: / Line 30: @@
 </div>
 <div class="pdbe-citations 3gur" style="background-color:#fffaf0;"></div>
-==See Also==
-*[[Glutathione S-transferase|Glutathione S-transferase]]
 == References ==
 <references/>

3gur

From Proteopedia

Revision as of 07:13, 1 November 2017

Crystal Structure of mu class glutathione S-transferase (GSTM2-2) in complex with glutathione and 6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX)

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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