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4zbk

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Crystal Structure of human GGT1 in complex with GGsTop inhibitor

Structural highlights

4zbk 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 2.18Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

GGT1_HUMAN Gamma-glutamyl transpeptidase deficiency. The disease is caused by mutations affecting the gene represented in this entry.

Function

GGT1_HUMAN Initiates extracellular glutathione (GSH) breakdown, provides cells with a local cysteine supply and contributes to maintain intracellular GSH level. It is part of the cell antioxidant defense mechanism. Catalyzes the transfer of the glutamyl moiety of glutathione to amino acids and dipeptide acceptors. Alternatively, glutathione can be hydrolyzed to give Cys-Gly and gamma glutamate. Isoform 3 seems to be inactive.^[1] ^[2]

Publication Abstract from PubMed

Gamma-glutamyl transpeptidase 1 (GGT1) is a cell surface, N-terminal nucleophile hydrolase that cleaves glutathione and other gamma-glutamyl compounds. GGT1 expression is essential in cysteine homeostasis and its induction has been implicated in the pathology of asthma, reperfusion injury and cancer. In this study, we report four new crystal structures of human GGT1 (hGGT1) which show conformational changes within the active site as the enzyme progresses from the free enzyme to inhibitor-bound tetrahedral transition states and finally to the glutamate-bound structure prior to the release of this final product of the reaction. The structure of the apo-enzyme shows flexibility within the active site. The serine-borate-bound hGGT1 crystal structure demonstrates that serine-borate occupies the active site of enzyme resulting in an enzyme-inhibitor complex that replicates the enzymes tetrahedral intermediate/transition state. The structure of GGsTop-bound hGGT1 reveals its interactions with the enzyme and why neutral phosphonate diesters are more potent inhibitors than mono-anionic phosphonates. These structures are the first structures for any eukaryotic GGT that include a molecule in the active site covalently bound to the catalytic Thr381. The glutamate-bound structure shows the conformation of the enzyme prior to release of the final product and revealed novel information regarding the displacement of the main chain atoms that form the oxyanion hole and movement of the lid loop region when the active site is occupied. These data provide new insights into the mechanism of hGGT1-catalyzed reactions and will be invaluable in the development of new classes of hGGT1 inhibitors for therapeutic use.

Human Gamma-Glutamyl Transpeptidase 1: Structures of the Free Enzyme, Inhibitor-Bound Tetrahedral Transition States and Glutamate-Bound Enzyme Reveal Novel Movement within the Active Site during Catalysis.,Terzyan SS, Burgett AW, Heroux A, Smith CA, Mooers BH, Hanigan MH J Biol Chem. 2015 May 26. pii: jbc.M115.659680. PMID:26013825^[3]

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

References

↑ Wetmore LA, Gerard C, Drazen JM. Human lung expresses unique gamma-glutamyl transpeptidase transcripts. Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7461-5. PMID:7689219
↑ West MB, Segu ZM, Feasley CL, Kang P, Klouckova I, Li C, Novotny MV, West CM, Mechref Y, Hanigan MH. Analysis of site-specific glycosylation of renal and hepatic gamma-glutamyl transpeptidase from normal human tissue. J Biol Chem. 2010 Sep 17;285(38):29511-24. doi: 10.1074/jbc.M110.145938. Epub, 2010 Jul 9. PMID:20622017 doi:10.1074/jbc.M110.145938
↑ Terzyan SS, Burgett AW, Heroux A, Smith CA, Mooers BH, Hanigan MH. Human Gamma-Glutamyl Transpeptidase 1: Structures of the Free Enzyme, Inhibitor-Bound Tetrahedral Transition States and Glutamate-Bound Enzyme Reveal Novel Movement within the Active Site during Catalysis. J Biol Chem. 2015 May 26. pii: jbc.M115.659680. PMID:26013825 doi:http://dx.doi.org/10.1074/jbc.M115.659680

1 Structural highlights
2 Disease
3 Function
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/4zbk"

Categories: Homo sapiens | Large Structures | Hanigan M | Terzyan S

@@ Line 1: / Line 1: @@
 ==Crystal Structure of human GGT1 in complex with GGsTop inhibitor==
-<StructureSection load='4zbk' size='340' side='right' caption='[[4zbk]], [[Resolution|resolution]] 2.18&Aring;' scene=''>
+<StructureSection load='4zbk' size='340' side='right'caption='[[4zbk]], [[Resolution|resolution]] 2.18&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4zbk]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZBK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZBK FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4zbk]] 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=4ZBK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZBK FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4M8:(2S)-2-AMINO-4-[(S)-HYDROXY(METHOXY)PHOSPHORYL]BUTANOIC+ACID'>4M8</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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]] 2.18&#8491;</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=4zbk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zbk OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4zbk RCSB], [http://www.ebi.ac.uk/pdbsum/4zbk PDBsum]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4M8:(2S)-2-AMINO-4-[(S)-HYDROXY(METHOXY)PHOSPHORYL]BUTANOIC+ACID'>4M8</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=4zbk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zbk OCA], [https://pdbe.org/4zbk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zbk RCSB], [https://www.ebi.ac.uk/pdbsum/4zbk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zbk ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/GGT1_HUMAN GGT1_HUMAN]] Gamma-glutamyl transpeptidase deficiency. The disease is caused by mutations affecting the gene represented in this entry.
+[https://www.uniprot.org/uniprot/GGT1_HUMAN GGT1_HUMAN] Gamma-glutamyl transpeptidase deficiency. The disease is caused by mutations affecting the gene represented in this entry.
 == Function ==
-[[http://www.uniprot.org/uniprot/GGT1_HUMAN GGT1_HUMAN]] Initiates extracellular glutathione (GSH) breakdown, provides cells with a local cysteine supply and contributes to maintain intracellular GSH level. It is part of the cell antioxidant defense mechanism. Catalyzes the transfer of the glutamyl moiety of glutathione to amino acids and dipeptide acceptors. Alternatively, glutathione can be hydrolyzed to give Cys-Gly and gamma glutamate. Isoform 3 seems to be inactive.<ref>PMID:7689219</ref> <ref>PMID:20622017</ref>
+[https://www.uniprot.org/uniprot/GGT1_HUMAN GGT1_HUMAN] Initiates extracellular glutathione (GSH) breakdown, provides cells with a local cysteine supply and contributes to maintain intracellular GSH level. It is part of the cell antioxidant defense mechanism. Catalyzes the transfer of the glutamyl moiety of glutathione to amino acids and dipeptide acceptors. Alternatively, glutathione can be hydrolyzed to give Cys-Gly and gamma glutamate. Isoform 3 seems to be inactive.<ref>PMID:7689219</ref> <ref>PMID:20622017</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 18: / Line 20: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4zbk" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Hanigan, M]]
+[[Category: Homo sapiens]]
-[[Category: Terzyan, S]]
+[[Category: Large Structures]]
-[[Category: Cell surface]]
+[[Category: Hanigan M]]
-[[Category: Enzyme inhibitor complex]]
+[[Category: Terzyan S]]
-[[Category: Hydrolase]]
-[[Category: Hydrolase-hydrolase inhibitor complex]]
-[[Category: N- glycosylation]]
-[[Category: Ntn-hydrolase family]]

4zbk

From Proteopedia

Current revision

Crystal Structure of human GGT1 in complex with GGsTop inhibitor

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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