8v9m: Difference between revisions

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-'''Unreleased structure'''
-The entry 8v9m is ON HOLD  until Paper Publication
+==Human Ornithine Aminotransferase cocrystallized with its inhibitor, (R)-3-amino-5,5-difluorocyclohex-1-ene-1-carboxylic acid.==
+<StructureSection load='8v9m' size='340' side='right'caption='[[8v9m]], [[Resolution|resolution]] 1.61&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8v9m]] 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=8V9M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8V9M 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]] 1.61&#8491;</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=YR5:3-fluoro-5-[({3-hydroxy-2-methyl-5-[(phosphonooxy)methyl]pyridin-4-yl}methyl)amino]benzoic+acid'>YR5</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=8v9m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8v9m OCA], [https://pdbe.org/8v9m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8v9m RCSB], [https://www.ebi.ac.uk/pdbsum/8v9m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8v9m 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 ==
+Human ornithine aminotransferase (hOAT), a pyridoxal 5'-phosphate (PLP)-dependent enzyme, has been shown to play an essential role in the metabolic reprogramming and progression of hepatocellular carcinoma (HCC). HCC accounts for approximately 75% of primary liver cancers and is within the top three causes of cancer death worldwide. As a result of treatment limitations, the overall 5-year survival rate for all patients with HCC is under 20%. The prevalence of HCC necessitates continued development of novel and effective treatment methods. In recent years, the therapeutic potential of selective inactivation of hOAT has been demonstrated for the treatment of HCC. Inspired by previous increased selectivity for hOAT by the expansion of the cyclopentene ring scaffold to a cyclohexene, we designed, synthesized, and evaluated a series of novel fluorinated cyclohexene analogues and identified (R)-3-amino-5,5-difluorocyclohex-1-ene-1-carboxylic acid as a time-dependent inhibitor of hOAT. Structural and mechanistic studies have elucidated the mechanism of inactivation of hOAT by 5, resulting in a PLP-inactivator adduct tightly bound to the active site of the enzyme. Intact protein mass spectrometry, (19)F NMR spectroscopy, transient state kinetic studies, and X-ray crystallography were used to determine the structure of the final adduct and elucidate the mechanisms of inactivation. Interestingly, despite the highly electrophilic intermediate species conferred by fluorine and structural evidence of solvent accessibility in the hOAT active site, Lys292 and water did not participate in nucleophilic addition during the inactivation mechanism of hOAT by 5. Instead, rapid aromatization to yield the final adduct was favored.
-Authors: Vargas, A.L., Devitt, A., Kaley, N., Silverman, R., Liu, D.
+Design, Synthesis, and Mechanistic Studies of (R)-3-Amino-5,5-difluorocyclohex-1-ene-1-carboxylic Acid as an Inactivator of Human Ornithine Aminotransferase.,Devitt AN, Vargas AL, Zhu W, Des Soye BJ, Butun FA, Alt T, Kaley N, Ferreira GM, Moran GR, Kelleher NL, Liu D, Silverman RB ACS Chem Biol. 2024 Apr 17. doi: 10.1021/acschembio.4c00022. PMID:38630468<ref>PMID:38630468</ref>
-Description: Human Ornithine Aminotransferase cocrystallized with its inhibitor, (R)-3-amino-5,5-difluorocyclohex-1-ene-1-carboxylic acid.
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Kaley, N]]
+<div class="pdbe-citations 8v9m" style="background-color:#fffaf0;"></div>
-[[Category: Liu, D]]
+== References ==
-[[Category: Vargas, A.L]]
+<references/>
-[[Category: Devitt, A]]
+__TOC__
-[[Category: Silverman, R]]
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Devitt A]]
+[[Category: Kaley N]]
+[[Category: Liu D]]
+[[Category: Silverman R]]
+[[Category: Vargas AL]]