View source for 7jx9


==The crystal structure of human ornithine aminotransferase with an intermediate bound during inactivation by (1S,3S)-3-amino-4-(hexafluoropropan-2-ylidenyl)-cyclopentane-1-carboxylic acid.==
<StructureSection load='7jx9' size='340' side='right'caption='[[7jx9]], [[Resolution|resolution]] 1.96&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7jx9]] is a 3 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=7JX9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JX9 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]] 1.96&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IF1:(1S,3S,4S)-3-[(E)-({3-hydroxy-2-methyl-5-[(phosphonooxy)methyl]pyridin-4-yl}methylidene)amino]-4-(1,1,3,3,3-pentafluoroprop-1-en-2-yl)cyclopentane-1-carboxylic+acid'>IF1</scene>, <scene name='pdbligand=VLS:N-[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]glycine'>VLS</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=7jx9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jx9 OCA], [https://pdbe.org/7jx9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jx9 RCSB], [https://www.ebi.ac.uk/pdbsum/7jx9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jx9 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/OAT_HUMAN OAT_HUMAN] Defects in OAT are the cause of hyperornithinemia with gyrate atrophy of choroid and retina (HOGA) [MIM:[https://omim.org/entry/258870 258870]. HOGA is a slowly progressive blinding autosomal recessive disorder.<ref>PMID:3375240</ref> <ref>PMID:2793865</ref> <ref>PMID:1612597</ref> <ref>PMID:1737786</ref> <ref>PMID:7887415</ref> <ref>PMID:7668253</ref> 
== Function ==
[https://www.uniprot.org/uniprot/OAT_HUMAN OAT_HUMAN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Hepatocellular carcinoma (HCC) is the most common form of liver cancer and the leading cause of death among people with cirrhosis. HCC is typically diagnosed in advanced stages when tumors are resistant to both radio- and chemotherapy. Human ornithine aminotransferase (hOAT) is a pyridoxal-5'-phosphate (PLP)-dependent enzyme involved in glutamine and proline metabolism. Because hOAT is overexpressed in HCC cells and a contributing factor for the uncontrolled cellular division that propagates malignant tumors (Ueno et al. J. Hepatol. 2014, 61, 1080-1087), it is a potential drug target for the treatment of HCC. (1S,3S)-3-Amino-4-(hexafluoropropan-2-ylidenyl)-cyclopentane-1-carboxylic acid (BCF3) has been shown in animal models to slow the progression of HCC by acting as a selective and potent mechanism-based inactivator of OAT (Zigmond et al. ACS Med. Chem. Lett. 2015, 6, 840-844). Previous studies have shown that the BCF3-hOAT reaction has a bifurcation in which only 8% of the inhibitor inactivates the enzyme while the remaining 92% ultimately acts as a substrate and undergoes hydrolysis to regenerate the active PLP form of the enzyme. In this manuscript, the rate-limiting step of the inactivation mechanism was determined by stopped-flow spectrophotometry and time-dependent (19)F NMR experiments to be the decay of a long-lived external aldimine species. A crystal structure of this transient complex revealed both the structural basis for fractional irreversible inhibition and the principal mode of inhibition of hOAT by BCF3, which is to trap the enzyme in this transient but quasi-stable external aldimine form.

Structural and Kinetic Analyses Reveal the Dual Inhibition Modes of Ornithine Aminotransferase by (1S,3S)-3-Amino-4-(hexafluoropropan-2-ylidenyl)-cyclopentane-1-carboxylic Acid (BCF3).,Butrin A, Beaupre BA, Kadamandla N, Zhao P, Shen S, Silverman RB, Moran GR, Liu D ACS Chem Biol. 2020 Dec 14. doi: 10.1021/acschembio.0c00728. PMID:33316155<ref>PMID:33316155</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7jx9" style="background-color:#fffaf0;"></div>

==See Also==
*[[Aminotransferase 3D structures|Aminotransferase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Beaupre B]]
[[Category: Butrin A]]
[[Category: Liu D]]
[[Category: Moran G]]
[[Category: Shen S]]
[[Category: Silverman RB]]