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6dnb

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Crystal structure of T110A:S256A mutant human Glutamate oxaloacetate transaminase 1 (GOT1)

Structural highlights

6dnb is a 1 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 1.7Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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.

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

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/6dnb"

@@ Line 1: / Line 1: @@
 ==Crystal structure of T110A:S256A mutant human Glutamate oxaloacetate transaminase 1 (GOT1)==
-<StructureSection load='6dnb' size='340' side='right' caption='[[6dnb]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
+<StructureSection load='6dnb' size='340' side='right'caption='[[6dnb]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6dnb]] is a 1 chain structure. 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]] 1.7&#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=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='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'>[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>
 == 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;">
 == Publication Abstract from PubMed ==
@@ Line 18: / Line 19: @@
 </div>
 <div class="pdbe-citations 6dnb" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Aspartate aminotransferase 3D structures|Aspartate aminotransferase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Assar, Z]]
+[[Category: Homo sapiens]]
-[[Category: Holt, M C]]
+[[Category: Large Structures]]
-[[Category: Lairson, L]]
+[[Category: Assar Z]]
-[[Category: Lyssiotis, C A]]
+[[Category: Holt MC]]
-[[Category: Stein, A J]]
+[[Category: Lairson L]]
-[[Category: Aspartate aminotransferase]]
+[[Category: Lyssiotis CA]]
-[[Category: Glutamate oxaloacetate transaminase 1]]
+[[Category: Stein AJ]]
-[[Category: Got1]]
-[[Category: Plp]]
-[[Category: Transferase]]

6dnb

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Current revision

Crystal structure of T110A:S256A mutant human Glutamate oxaloacetate transaminase 1 (GOT1)

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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