|
|
| (One intermediate revision not shown.) |
| Line 1: |
Line 1: |
| | | | |
| | ==Crystal Structure of human GGT1 in complex with DON== | | ==Crystal Structure of human GGT1 in complex with DON== |
| - | <StructureSection load='5v4q' size='340' side='right' caption='[[5v4q]], [[Resolution|resolution]] 2.20Å' scene=''> | + | <StructureSection load='5v4q' size='340' side='right'caption='[[5v4q]], [[Resolution|resolution]] 2.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5v4q]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5V4Q OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5V4Q FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5v4q]] 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=5V4Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5V4Q FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8WY:5,5-DIHYDROXY-L-NORLEUCINE'>8WY</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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]] 2.2Å</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=5v4q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v4q OCA], [http://pdbe.org/5v4q PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5v4q RCSB], [http://www.ebi.ac.uk/pdbsum/5v4q PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5v4q ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8WY:5,5-DIHYDROXY-L-NORLEUCINE'>8WY</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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=5v4q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v4q OCA], [https://pdbe.org/5v4q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5v4q RCSB], [https://www.ebi.ac.uk/pdbsum/5v4q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5v4q ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == 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 == | | == 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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 24: |
Line 25: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Hanigan, M]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Terzyan, S]] | + | [[Category: Large Structures]] |
| - | [[Category: Cell surface]] | + | [[Category: Hanigan M]] |
| - | [[Category: Glycoprotein]] | + | [[Category: Terzyan S]] |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: N- glycosylation]]
| + | |
| - | [[Category: Ntn-hydrolase family]]
| + | |
| Structural highlights
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
Intense efforts are underway to identify inhibitors of the enzyme gamma-glutamyl transpeptidase 1 (GGT1) which cleaves extracellular gamma-glutamyl compounds and contributes to the pathology of asthma, reperfusion injury and cancer. The glutamate analog, 6-diazo-5-oxo-norleucine (DON), inhibits GGT1. DON also inhibits many essential glutamine metabolizing enzymes rendering it too toxic for use in the clinic as a GGT1 inhibitor. We investigated the molecular mechanism of human GGT1 (hGGT1) inhibition by DON to determine possible strategies for increasing its specificity for hGGT1. DON is an irreversible inhibitor of hGGT1. The second order rate constant of inactivation was 0.052 mM-1 min-1 and the Ki was 2.7 +/- 0.7 mM. The crystal structure of DON-inactivated hGGT1 contained a molecule of DON without the diazo-nitrogen atoms in the active site. The overall structure of the hGGT1-DON complex resembled the structure of the apo-enzyme; however, shifts were detected in the loop forming the oxyanion hole and elements of the main chain that form the entrance to the active site. The structure of hGGT1-DON complex revealed two covalent bonds between the enzyme and inhibitor which were part of a six membered ring. The ring included the OG atom of Thr381, the reactive nucleophile of hGGT1 and the alpha-amine of Thr381. The structure of DON-bound hGGT1 has led to the discovery of a new mechanism of inactivation by DON that differs from its inactivation of other glutamine metabolizing enzymes, and insight into the activation of the catalytic nucleophile that initiates the hGGT1 reaction.
Structure of 6-diazo-5-oxo-norleucine-bound human gamma-glutamyl transpeptidase 1, a novel mechanism of inactivation.,Terzyan SS, Cook PF, Heroux A, Hanigan MH Protein Sci. 2017 Apr 5. doi: 10.1002/pro.3172. PMID:28378915[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, Cook PF, Heroux A, Hanigan MH. Structure of 6-diazo-5-oxo-norleucine-bound human gamma-glutamyl transpeptidase 1, a novel mechanism of inactivation. Protein Sci. 2017 Apr 5. doi: 10.1002/pro.3172. PMID:28378915 doi:http://dx.doi.org/10.1002/pro.3172
|
