6w4c: Difference between revisions
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==Crystal structure of HAO1 in complex with indazole acid inhibitor - compound 5== | ==Crystal structure of HAO1 in complex with indazole acid inhibitor - compound 5== | ||
<StructureSection load='6w4c' size='340' side='right'caption='[[6w4c]]' scene=''> | <StructureSection load='6w4c' size='340' side='right'caption='[[6w4c]], [[Resolution|resolution]] 1.75Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6W4C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6W4C FirstGlance]. <br> | <table><tr><td colspan='2'>[[6w4c]] is a 1 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=6W4C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6W4C FirstGlance]. <br> | ||
</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=6w4c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w4c OCA], [https://pdbe.org/6w4c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6w4c RCSB], [https://www.ebi.ac.uk/pdbsum/6w4c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6w4c ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.75Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=SL7:5-[[3-[3-(dimethylamino)-1,2,4-oxadiazol-5-yl]-2-oxidanyl-phenyl]methylamino]-2~{H}-indazole-3-carboxylic+acid'>SL7</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=6w4c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w4c OCA], [https://pdbe.org/6w4c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6w4c RCSB], [https://www.ebi.ac.uk/pdbsum/6w4c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6w4c ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/HAOX1_HUMAN HAOX1_HUMAN] Has 2-hydroxyacid oxidase activity. Most active on the 2-carbon substrate glycolate, but is also active on 2-hydroxy fatty acids, with high activity towards 2-hydroxy palmitate and 2-hydroxy octanoate. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Inhibition of hydroxy acid oxidase 1 (HAO1) is a strategy to mitigate the accumulation of toxic oxalate that results from reduced activity of alanine-glyoxylate aminotransferase (AGXT) in primary hyperoxaluria 1 (PH1) patients. DNA-Encoded Chemical Library (DECL) screening provided two novel chemical series of potent HAO1 inhibitors, represented by compounds 3-6. Compound 5 was further optimized via various structure-activity relationship (SAR) exploration methods to 29, a compound with improved potency and absorption, distribution, metabolism, and excretion (ADME)/pharmacokinetic (PK) properties. Since carboxylic acid-containing compounds are often poorly permeable and have potential active glucuronide metabolites, we undertook a brief, initial exploration of acid replacements with the aim of identifying non-acid-containing HAO1 inhibitors. Structure-based drug design initiated with Compound 5 led to the identification of a nonacid inhibitor of HAO1, 31, which has weaker potency and increased permeability. | |||
Discovery of Novel, Potent Inhibitors of Hydroxy Acid Oxidase 1 (HAO1) Using DNA-Encoded Chemical Library Screening.,Lee ECY, McRiner AJ, Georgiadis KE, Liu J, Wang Z, Ferguson AD, Levin B, von Rechenberg M, Hupp CD, Monteiro MI, Keefe AD, Olszewski A, Eyermann CJ, Centrella P, Liu Y, Arora S, Cuozzo JW, Zhang Y, Clark MA, Huguet C, Kohlmann A J Med Chem. 2021 May 6. doi: 10.1021/acs.jmedchem.0c02271. PMID:33955740<ref>PMID:33955740</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6w4c" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Glycolate oxidase 3D structures|Glycolate oxidase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Ferguson AD]] | [[Category: Ferguson AD]] | ||