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5vwr

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(New page: ==E.coli Aspartate aminotransferase-(1R,3S,4S)-3-amino-4-fluorocyclopentane-1-carboxylic acid (FCP)-alpha-ketoglutarate== <StructureSection load='5vwr' size='340' side='right' caption='[[...)
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==E.coli Aspartate aminotransferase-(1R,3S,4S)-3-amino-4-fluorocyclopentane-1-carboxylic acid (FCP)-alpha-ketoglutarate==
==E.coli Aspartate aminotransferase-(1R,3S,4S)-3-amino-4-fluorocyclopentane-1-carboxylic acid (FCP)-alpha-ketoglutarate==
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<StructureSection load='5vwr' size='340' side='right' caption='[[5vwr]], [[Resolution|resolution]] 1.72&Aring;' scene=''>
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<StructureSection load='5vwr' size='340' side='right'caption='[[5vwr]], [[Resolution|resolution]] 1.72&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5vwr]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5VWR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5VWR FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5vwr]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5VWR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5VWR FirstGlance]. <br>
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</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=PL6:(E)-N-({3-HYDROXY-2-METHYL-5-[(PHOSPHONOOXY)METHYL]PYRIDIN-4-YL}METHYLIDENE)-L-GLUTAMIC+ACID'>PL6</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.72&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5vwo|5vwo]], [[5vwq|5vwq]]</td></tr>
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<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=PL6:(E)-N-({3-HYDROXY-2-METHYL-5-[(PHOSPHONOOXY)METHYL]PYRIDIN-4-YL}METHYLIDENE)-L-GLUTAMIC+ACID'>PL6</scene></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Aspartate_transaminase Aspartate transaminase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.6.1.1 2.6.1.1] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5vwr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vwr OCA], [https://pdbe.org/5vwr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5vwr RCSB], [https://www.ebi.ac.uk/pdbsum/5vwr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5vwr ProSAT]</span></td></tr>
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<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=5vwr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vwr OCA], [http://pdbe.org/5vwr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5vwr RCSB], [http://www.ebi.ac.uk/pdbsum/5vwr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5vwr ProSAT]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/AAT_ECOLI AAT_ECOLI]
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Potent mechanism-based inactivators can be rationally designed against PLP-dependent drug targets, such as ornithine aminotransferase (OAT) or gamma-aminobutyric acid aminotransferase (GABA-AT). An important challenge, however, is the lack of selectivity towards other PLP-dependent off-target enzymes, because of similarities in mechanisms of all PLP-dependent aminotransferase reactions. On the basis of complex crystal structures, we investigate the inactivation mechanism of OAT, a hepatocellular carcinoma (HCC) target, by (1R,3S,4S)-3-amino-4-fluorocyclopentane-1-carboxylic acid (FCP), a known inactivator of GABA-AT. A crystal structure of OAT and FCP showed the formation of a ternary adduct. This adduct can be rationalized as occurring via an enamine mechanism of inactivation similar to that reported for GABA-AT. However, the crystal structure of an off-target PLP-dependent enzyme, aspartate aminotransferase (Asp-AT), in complex with FCP, along with the results of attempted inhibition assays, suggest that FCP is not an inactivator of Asp-AT, but rather an alternate substrate. Turnover of FCP by Asp-AT is also supported by high-resolution mass spectrometry. In comparison to the inactivation mechanisms of FCP against OAT and GABA-AT, the obtained results provide evidence that a desirable selectivity of inactivation could be achieved, taking advantage of subtle structural and mechanistic differences between a drug-target and an off-target enzyme, despite their largely similar substrate binding sites and catalytic mechanisms.
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Selective Targeting by a Mechanism-based Inactivator against PLP-Dependent Enzymes: Mechanisms of Inactivation and Alternative Turnover.,Mascarenhas R, Le HV, Clevenger KD, Lehrer HJ, Ringe D, Kelleher NL, Silverman RB, Liu D Biochemistry. 2017 Aug 17. doi: 10.1021/acs.biochem.7b00499. PMID:28816437<ref>PMID:28816437</ref>
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==See Also==
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*[[Aspartate aminotransferase 3D structures|Aspartate aminotransferase 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 5vwr" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Aspartate transaminase]]
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[[Category: Escherichia coli K-12]]
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[[Category: Le, H]]
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[[Category: Large Structures]]
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[[Category: Liu, D]]
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[[Category: Le H]]
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[[Category: Mascarenhas, R]]
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[[Category: Liu D]]
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[[Category: Silverman, R]]
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[[Category: Mascarenhas R]]
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[[Category: 3]]
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[[Category: Silverman R]]
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[[Category: Alpha-ketoglutarate]]
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[[Category: Aspartate aminotransferase]]
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[[Category: Ketimine]]
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[[Category: Mechanism-based inactivator]]
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[[Category: Transferase]]
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Current revision

E.coli Aspartate aminotransferase-(1R,3S,4S)-3-amino-4-fluorocyclopentane-1-carboxylic acid (FCP)-alpha-ketoglutarate

PDB ID 5vwr

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