View source for 5vwq


==E.coli Aspartate aminotransferase-(1R,3S,4S)-3-amino-4-fluorocyclopentane-1-carboxylic acid (FCP)==
<StructureSection load='5vwq' size='340' side='right'caption='[[5vwq]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5vwq]] is a 4 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=5VWQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5VWQ FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PMP:4-DEOXY-4-AMINOPYRIDOXAL-5-PHOSPHATE'>PMP</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=5vwq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vwq OCA], [https://pdbe.org/5vwq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5vwq RCSB], [https://www.ebi.ac.uk/pdbsum/5vwq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5vwq ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/AAT_ECOLI AAT_ECOLI] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.

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>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5vwq" style="background-color:#fffaf0;"></div>

==See Also==
*[[Aspartate aminotransferase 3D structures|Aspartate aminotransferase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Escherichia coli K-12]]
[[Category: Large Structures]]
[[Category: Lehrer H]]
[[Category: Liu D]]
[[Category: Mascarenhas R]]
[[Category: Ringe D]]