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| | ==Crystal structure of T110A:S256A mutant human Glutamate oxaloacetate transaminase 1 (GOT1)== | | ==Crystal structure of T110A:S256A mutant human Glutamate oxaloacetate transaminase 1 (GOT1)== |
| - | <StructureSection load='6dnb' size='340' side='right' caption='[[6dnb]], [[Resolution|resolution]] 1.70Å' scene=''> | + | <StructureSection load='6dnb' size='340' side='right'caption='[[6dnb]], [[Resolution|resolution]] 1.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6dnb]] is a 1 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=6DNB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DNB FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6dnb]] is a 1 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=6DNB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DNB FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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]] 1.7Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GOT1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></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=6dnb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dnb OCA], [http://pdbe.org/6dnb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dnb RCSB], [http://www.ebi.ac.uk/pdbsum/6dnb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dnb ProSAT]</span></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=6dnb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dnb OCA], [https://pdbe.org/6dnb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6dnb RCSB], [https://www.ebi.ac.uk/pdbsum/6dnb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6dnb ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/AATC_HUMAN AATC_HUMAN]] Plays a key role in amino acid metabolism (By similarity). | + | [https://www.uniprot.org/uniprot/AATC_HUMAN AATC_HUMAN] Plays a key role in amino acid metabolism (By similarity). |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6dnb" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6dnb" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Aspartate aminotransferase 3D structures|Aspartate aminotransferase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Assar, Z]] | + | [[Category: Large Structures]] |
| - | [[Category: Holt, M C]] | + | [[Category: Assar Z]] |
| - | [[Category: Lairson, L]] | + | [[Category: Holt MC]] |
| - | [[Category: Lyssiotis, C A]] | + | [[Category: Lairson L]] |
| - | [[Category: Stein, A J]] | + | [[Category: Lyssiotis CA]] |
| - | [[Category: Aspartate aminotransferase]]
| + | [[Category: Stein AJ]] |
| - | [[Category: Glutamate oxaloacetate transaminase 1]]
| + | |
| - | [[Category: Got1]]
| + | |
| - | [[Category: Plp]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
AATC_HUMAN Plays a key role in amino acid metabolism (By similarity).
Publication Abstract from PubMed
Pancreatic cancer cells are characterized by deregulated metabolic programs that facilitate growth and resistance to oxidative stress. Among these programs, pancreatic cancers preferentially utilize a metabolic pathway through the enzyme aspartate aminotransferase 1 [also known as glutamate oxaloacetate transaminase 1 (GOT1)] to support cellular redox homeostasis. As such, small molecule inhibitors that target GOT1 could serve as starting points for the development of new therapies for pancreatic cancer. We ran a high-throughput screen for inhibitors of GOT1 and identified a small molecule, iGOT1-01, with in vitro GOT1 inhibitor activity. Application in pancreatic cancer cells revealed metabolic and growth inhibitory activity reflecting a promiscuous inhibitory profile. We then performed an in silico docking analysis to study inhibitor-GOT1 interactions with iGOT1-01 analogues that possess improved solubility and potency properties. These results suggested that the GOT1 inhibitor competed for binding to the pyridoxal 5-phosphate (PLP) cofactor site of GOT1. To analyze how the GOT1 inhibitor bound to GOT1, a series of GOT1 mutant enzymes that abolished PLP binding were generated. Application of the mutants in X-ray crystallography and thermal shift assays again suggested but were unable to formally conclude that the GOT1 inhibitor bound to the PLP site. Mutational studies revealed the relationship between PLP binding and the thermal stability of GOT1 while highlighting the essential nature of several residues for GOT1 catalytic activity. Insight into the mode of action of GOT1 inhibitors may provide leads to the development of drugs that target redox balance in pancreatic cancer.
Biochemical Characterization and Structure-Based Mutational Analysis Provide Insight into the Binding and Mechanism of Action of Novel Aspartate Aminotransferase Inhibitors.,Holt MC, Assar Z, Beheshti Zavareh R, Lin L, Anglin J, Mashadova O, Haldar D, Mullarky E, Kremer DM, Cantley LC, Kimmelman AC, Stein AJ, Lairson LL, Lyssiotis CA Biochemistry. 2018 Nov 12. doi: 10.1021/acs.biochem.8b00914. PMID:30365304[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Holt MC, Assar Z, Beheshti Zavareh R, Lin L, Anglin J, Mashadova O, Haldar D, Mullarky E, Kremer DM, Cantley LC, Kimmelman AC, Stein AJ, Lairson LL, Lyssiotis CA. Biochemical Characterization and Structure-Based Mutational Analysis Provide Insight into the Binding and Mechanism of Action of Novel Aspartate Aminotransferase Inhibitors. Biochemistry. 2018 Nov 12. doi: 10.1021/acs.biochem.8b00914. PMID:30365304 doi:http://dx.doi.org/10.1021/acs.biochem.8b00914
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