8im3

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Current revision (14:08, 18 October 2023) (edit) (undo)
 
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'''Unreleased structure'''
 
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The entry 8im3 is ON HOLD until Paper Publication
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==Crystal structure of human HPPD complexed with compound a10==
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<StructureSection load='8im3' size='340' side='right'caption='[[8im3]], [[Resolution|resolution]] 2.78&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[8im3]] is a 6 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=8IM3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8IM3 FirstGlance]. <br>
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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]] 2.78&#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=92U:[1,3-diethyl-2,2-bis(oxidanylidene)-2$l^{6},1,3-benzothiadiazol-5-yl]-(1-methyl-5-oxidanyl-pyrazol-4-yl)methanone'>92U</scene>, <scene name='pdbligand=CO:COBALT+(II)+ION'>CO</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=8im3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8im3 OCA], [https://pdbe.org/8im3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8im3 RCSB], [https://www.ebi.ac.uk/pdbsum/8im3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8im3 ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/HPPD_HUMAN HPPD_HUMAN] Defects in HPD are the cause of tyrosinemia type 3 (TYRO3) [MIM:[https://omim.org/entry/276710 276710]. TYRO3 is an inborn error of metabolism characterized by elevations of tyrosine in the blood and urine, seizures and mild mental retardation.<ref>PMID:10942115</ref> <ref>PMID:11073718</ref> Defects in HPD are a cause of hawkinsinuria (HAWK) [MIM:[https://omim.org/entry/140350 140350]. HAWK is an inborn error of tyrosine metabolism characterized by failure to thrive, persistent metabolic acidosis, fine and sparse hair, and excretion of the unusual cyclic amino acid metabolite, hawkinsin, in the urine.<ref>PMID:11073718</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/HPPD_HUMAN HPPD_HUMAN] Key enzyme in the degradation of tyrosine.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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4-Hydroxyphenylpyruvate dioxygenase (HPPD) has attracted increasing attention as a target for treating type I tyrosinemia and other diseases with defects in tyrosine catabolism. Only one commercial drug, 2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione (NTBC), clinically treat type I tyrosinemia, but show some severe side effects in clinical application. Here, we determined the structure of human HPPD-NTBC complex, and developed new pyrazole-benzothiadiazole 2,2-dioxide hybrids from the binding of NTBC. These compounds showed improved inhibition against human HPPD, among which compound a10 was the most active candidate. The Absorption Distribution Metabolism Excretion Toxicity (ADMET) predicted properties suggested that a10 had good druggability, and was with lower toxicity than NTBC. The structure comparison between inhibitor-bound and ligand-free form human HPPD showed a large conformational change of the C-terminal helix. Furthermore, the loop 1 and alpha7 helix were found adopting different conformations to assist the gating of the cavity, which explains the gating mechanism of human HPPD.
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Authors: Dong, J., Lin, H.-Y.
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Structure-based discovery of pyrazole-benzothiadiazole hybrid as human HPPD inhibitors.,Dong J, Xiao H, Chen JN, Zheng BF, Xu YL, Chen MX, Yang WC, Lin HY, Yang GF Structure. 2023 Sep 21:S0969-2126(23)00328-3. doi: 10.1016/j.str.2023.09.005. PMID:37794595<ref>PMID:37794595</ref>
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Description: Crystal structure of human HPPD complexed with compound a10
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Lin, H.-Y]]
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<div class="pdbe-citations 8im3" style="background-color:#fffaf0;"></div>
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[[Category: Dong, J]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Dong J]]
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[[Category: Lin H-Y]]

Current revision

Crystal structure of human HPPD complexed with compound a10

PDB ID 8im3

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