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7pwy

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Current revision (13:10, 1 February 2024) (edit) (undo)
 
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==Structure of human dimeric ACMSD in complex with the inhibitor TES-1025==
==Structure of human dimeric ACMSD in complex with the inhibitor TES-1025==
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<StructureSection load='7pwy' size='340' side='right'caption='[[7pwy]]' scene=''>
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<StructureSection load='7pwy' size='340' side='right'caption='[[7pwy]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7PWY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7PWY FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7pwy]] is a 4 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=7PWY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7PWY FirstGlance]. <br>
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</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=7pwy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7pwy OCA], [https://pdbe.org/7pwy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7pwy RCSB], [https://www.ebi.ac.uk/pdbsum/7pwy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7pwy ProSAT]</span></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8EK:2-[3-[(5-cyano-6-oxidanylidene-4-thiophen-2-yl-1H-pyrimidin-2-yl)sulfanylmethyl]phenyl]ethanoic+acid'>8EK</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7pwy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7pwy OCA], [https://pdbe.org/7pwy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7pwy RCSB], [https://www.ebi.ac.uk/pdbsum/7pwy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7pwy ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
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[https://www.uniprot.org/uniprot/ACMSD_HUMAN ACMSD_HUMAN] Converts alpha-amino-beta-carboxymuconate-epsilon-semialdehyde (ACMS) to alpha-aminomuconate semialdehyde (AMS). ACMS can be converted non-enzymatically to quinolate (QA), a key precursor of NAD, and a potent endogenous excitotoxin of neuronal cells which is implicated in the pathogenesis of various neurodegenerative disorders. In the presence of ACMSD, ACMS is converted to AMS, a benign catabolite. ACMSD ultimately controls the metabolic fate of tryptophan catabolism along the kynurenine pathway.<ref>PMID:19843166</ref> <ref>PMID:12140278</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Human alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD) stands at a branch point of the de novo NAD(+) synthesis pathway and plays an important role in maintaining NAD(+) homeostasis. It has been recently identified as a novel therapeutic target for a wide range of diseases, including inflammatory, metabolic disorders, and aging. So far, in absence of potent and selective enzyme inhibitors, only a crystal structure of the complex of human dimeric ACMSD with pseudo-substrate dipicolinic acid has been resolved. In this study, we report the crystal structure of the complex of human dimeric ACMSD with TES-1025, the first nanomolar inhibitor of this target, which shows a binding conformation different from the previously published predicted binding mode obtained by docking experiments. The inhibitor has a K i value of 0.85 +/- 0.22 nM and binds in the catalytic site, interacting with the Zn(2+) metal ion and with residues belonging to both chains of the dimer. The results provide new structural information about the mechanism of inhibition exerted by a novel class of compounds on the ACMSD enzyme, a novel therapeutic target for liver and kidney diseases.
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Structural Basis of Human Dimeric alpha-Amino-beta-Carboxymuconate-epsilon-Semialdehyde Decarboxylase Inhibition With TES-1025.,Cianci M, Giacche N, Cialabrini L, Carotti A, Liscio P, Rosatelli E, De Franco F, Gasparrini M, Robertson J, Amici A, Raffaelli N, Pellicciari R Front Mol Biosci. 2022 Apr 7;9:834700. doi: 10.3389/fmolb.2022.834700., eCollection 2022. PMID:35463964<ref>PMID:35463964</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7pwy" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Amici A]]
[[Category: Amici A]]

Current revision

Structure of human dimeric ACMSD in complex with the inhibitor TES-1025

PDB ID 7pwy

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