12av: Difference between revisions

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'''Unreleased structure'''


The entry 12av is ON HOLD  until Paper Publication
==Human Ornithine Aminotransferase cocrystallized with its inhibitor,(3S,4S)-3-amino-4-cyanocyclopent-1-ene-1-carboxylic acid==
<StructureSection load='12av' size='340' side='right'caption='[[12av]], [[Resolution|resolution]] 1.51&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[12av]] is a 9 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=12AV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=12AV 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]] 1.51&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1DBF:4-cyano-3-[[2-methyl-3-oxidanyl-5-(phosphonooxymethyl)pyridin-4-yl]methylamino]cyclopenta-1,3-diene-1-carboxylic+acid'>A1DBF</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=12av FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=12av OCA], [https://pdbe.org/12av PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=12av RCSB], [https://www.ebi.ac.uk/pdbsum/12av PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=12av 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, plays a central role in glutamine, proline, and polyamine metabolism and is increasingly recognized as a metabolic vulnerability in multiple cancers. Previously, we established a second deprotonation strategy to achieve efficient mechanism-based inactivation of hOAT over closely related aminotransferases. Building on this concept, we report the rational design, synthesis, and mechanistic investigation of cyclopentene-based gamma-aminobutyric acid analogues bearing alkyne or nitrile warheads as potent hOAT inactivators. These compounds undergo enzyme-catalyzed gamma-deprotonation to form ketimine intermediates, priming for a subsequent tautomerization event that leads to irreversible inhibition. Inhibitory activity evaluation revealed pronounced stereochemical effects on binding affinity and partition ratio, with one nitrile analogue (4b) exhibiting an exceptional inactivation efficiency (k(inact)/K(I) = 111.8 mM(-1).min(-1)) and approximately 400-fold selectivity for hOAT over gamma-aminobutyric acid aminotransferase. Intact protein mass spectrometry and X-ray crystallography demonstrated that alkyne-containing analogues form covalent adducts with hOAT, whereas nitrile-containing analogues generate noncovalent but tight-binding species. Kinetic isotope effect studies identified gamma-deprotonation as the rate-determining step, and a complementary small-molecule mass and computational study elucidated the inactivation and turnover pathways. Collectively, these results expand the mechanistic repertoire of PLP-dependent enzyme inactivation and provide a generalizable framework for designing highly selective mechanism-based inactivators.


Authors: Corrigan, M.C., Wang, F., Silverman, R.B., Liu, D.
Mechanism-Based Inactivation of Human Ornithine Aminotransferase by Ethynyl- and Nitrile-Substituted Cyclopentene Analogues of gamma-Aminobutyric Acids.,Wang F, Corrigan MC, Le NHV, Duan D, Smith CO, Moran GR, Kelleher NL, Liu D, Silverman RB J Am Chem Soc. 2026 Jul 22;148(28):30301-30313. doi: 10.1021/jacs.6c08456. Epub , 2026 Jul 10. PMID:42429780<ref>PMID:42429780</ref>


Description: Human Ornithine Aminotransferase cocrystallized with its inhibitor,(3S,4S)-3-amino-4-cyanocyclopent-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: Liu, D]]
<div class="pdbe-citations 12av" style="background-color:#fffaf0;"></div>
[[Category: Corrigan, M.C]]
== References ==
[[Category: Silverman, R.B]]
<references/>
[[Category: Wang, F]]
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Corrigan MC]]
[[Category: Liu D]]
[[Category: Silverman RB]]
[[Category: Wang F]]
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