9y3m: Difference between revisions

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'''Unreleased structure'''


The entry 9y3m is ON HOLD
==Crystal Structure of Human Ornithine Aminotransferase Pre-inactivated by CPP115 (Covalent Inactivation)==
<StructureSection load='9y3m' size='340' side='right'caption='[[9y3m]], [[Resolution|resolution]] 1.73&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9y3m]] 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=9Y3M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9Y3M 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]] 1.73&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1CR8:(2S)-2-{(2Z)-2-[({3-hydroxy-2-methyl-5-[(phosphonooxy)methyl]pyridin-4-yl}methyl)imino]ethyl}pentanoic+acid'>A1CR8</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=9y3m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9y3m OCA], [https://pdbe.org/9y3m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9y3m RCSB], [https://www.ebi.ac.uk/pdbsum/9y3m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9y3m 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 ==
Currently, mechanism-based inactivators (MBIs) are the only available therapeutic option to target gamma-aminobutyric acid aminotransferase (GABA-AT). However, off-target activity against homologous enzymes is a well-recognized challenge for the clinical use of MBIs. For example, CPP-115, an MBI of GABA-AT that completed a Phase I clinical trial, also inactivates ornithine aminotransferase (OAT). Here, we present a comprehensive investigation of an OAT-specific inactivation mechanism for CPP-115 by integrating biochemical experiments, X-ray crystallography, and computational simulations. Unlike in GABA-AT, where CPP-115 forms a noncovalent tight-binding adduct only, a covalent adduct was additionally observed with human OAT (hOAT). Notably, the crystal structures of CPP-115-treated hOAT at different mechanistic stages indicate that the conformational transition of a key intermediate is a prerequisite for the covalent addition pathway. Based on this finding, to selectively reduce the off-target activity, a proof-of-concept molecule that regulates the intermediate conformational flexibility was designed and synthesized. The resulting inactivator achieved greatly enhanced GABA-AT selectivity over OAT and demonstrated therapeutic efficacy in an inflammatory pain animal model. Our strategy in this study, targeting dynamics of a reactive intermediate based on a precise mechanistic understanding, serves as a general design principle for fine-tuning the selectivity of MBIs, particularly for other aminotransferases.


Authors: Vargas, A.L., Kang, K.M., Corrigan, M.C., Liu, D., Silverman, R.B.
Targeting Conformational Flexibility of a Reactive Intermediate to Enhance Selectivity of a GABA Aminotransferase Inactivator.,Kang KM, Vargas AL, Ferreira LA, Des Soye BJ, Corrigan M, Zhang CK, Wang F, Duan D, Kelleher NL, Hohmann AG, Liu D, Silverman RB J Am Chem Soc. 2026 Mar 4;148(8):8736-8748. doi: 10.1021/jacs.5c21138. Epub 2026 , Feb 19. PMID:41711325<ref>PMID:41711325</ref>


Description: Crystal Structure of Human Ornithine Aminotransferase Pre-inactivated by CPP115 (Covalent Inactivation)
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
[[Category: Kang, K.M]]
<div class="pdbe-citations 9y3m" style="background-color:#fffaf0;"></div>
[[Category: Vargas, A.L]]
== References ==
[[Category: Silverman, R.B]]
<references/>
[[Category: Corrigan, M.C]]
__TOC__
[[Category: Liu, D]]
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Corrigan MC]]
[[Category: Kang KM]]
[[Category: Liu D]]
[[Category: Silverman RB]]
[[Category: Vargas AL]]
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