6zgv

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==Structure of human galactokinase 1 bound with 2-(4-chlorophenyl)-N-(pyrimidin-2-yl)acetamide==
==Structure of human galactokinase 1 bound with 2-(4-chlorophenyl)-N-(pyrimidin-2-yl)acetamide==
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<StructureSection load='6zgv' size='340' side='right'caption='[[6zgv]]' scene=''>
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<StructureSection load='6zgv' size='340' side='right'caption='[[6zgv]], [[Resolution|resolution]] 2.30&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=6ZGV OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZGV FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6zgv]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZGV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZGV FirstGlance]. <br>
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</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6zgv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zgv OCA], [http://pdbe.org/6zgv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6zgv RCSB], [http://www.ebi.ac.uk/pdbsum/6zgv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6zgv ProSAT]</span></td></tr>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GAL:BETA-D-GALACTOSE'>GAL</scene>, <scene name='pdbligand=HFK:2-(1,3-benzoxazol-2-ylamino)spiro[1,6,7,8-tetrahydroquinazoline-4,1-cyclohexane]-5-one'>HFK</scene>, <scene name='pdbligand=QKZ:2-(4-chlorophenyl)-~{N}-pyrimidin-2-yl-ethanamide'>QKZ</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GALK1, GALK ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Galactokinase Galactokinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.6 2.7.1.6] </span></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=6zgv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zgv OCA], [https://pdbe.org/6zgv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zgv RCSB], [https://www.ebi.ac.uk/pdbsum/6zgv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zgv ProSAT]</span></td></tr>
</table>
</table>
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== Disease ==
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[[https://www.uniprot.org/uniprot/GALK1_HUMAN GALK1_HUMAN]] Defects in GALK1 are the cause of galactosemia II (GALCT2) [MIM:[https://omim.org/entry/230200 230200]]. Galactosemia II is an autosomal recessive deficiency characterized by congenital cataracts during infancy and presenile cataracts in the adult population. The cataracts are secondary to accumulation of galactitol in the lenses.<ref>PMID:10521295</ref> <ref>PMID:10790206</ref> <ref>PMID:11231902</ref> <ref>PMID:11139256</ref> <ref>PMID:12694189</ref> <ref>PMID:15024738</ref>
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== Function ==
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[[https://www.uniprot.org/uniprot/GALK1_HUMAN GALK1_HUMAN]] Major enzyme for galactose metabolism.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Classic galactosemia is caused by loss-of-function mutations in galactose-1-phosphate uridylyltransferase (GALT) that lead to toxic accumulation of its substrate, galactose-1-phosphate. One proposed therapy is to inhibit the biosynthesis of galactose-1-phosphate, catalyzed by galactokinase 1 (GALK1). Existing inhibitors of human GALK1 (hGALK1) are primarily ATP-competitive with limited clinical utility to date. Here, we determined crystal structures of hGALK1 bound with reported ATP-competitive inhibitors of the spiro-benzoxazole series, to reveal their binding mode in the active site. Spurred by the need for additional chemotypes of hGALK1 inhibitors, desirably targeting a nonorthosteric site, we also performed crystallography-based screening by soaking hundreds of hGALK1 crystals, already containing active site ligands, with fragments from a custom library. Two fragments were found to bind close to the ATP binding site, and a further eight were found in a hotspot distal from the active site, highlighting the strength of this method in identifying previously uncharacterized allosteric sites. To generate inhibitors of improved potency and selectivity targeting the newly identified binding hotspot, new compounds were designed by merging overlapping fragments. This yielded two micromolar inhibitors of hGALK1 that were not competitive with respect to either substrate (ATP or galactose) and demonstrated good selectivity over hGALK1 homologues, galactokinase 2 and mevalonate kinase. Our findings are therefore the first to demonstrate inhibition of hGALK1 from an allosteric site, with potential for further development of potent and selective inhibitors to provide novel therapeutics for classic galactosemia.
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Fragment Screening Reveals Starting Points for Rational Design of Galactokinase 1 Inhibitors to Treat Classic Galactosemia.,Mackinnon SR, Krojer T, Foster WR, Diaz-Saez L, Tang M, Huber KVM, von Delft F, Lai K, Brennan PE, Arruda Bezerra G, Yue WW ACS Chem Biol. 2021 Mar 16. doi: 10.1021/acschembio.0c00498. PMID:33724769<ref>PMID:33724769</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 6zgv" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Galactokinase|Galactokinase]]
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Galactokinase]]
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[[Category: Human]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Arrowsmith C]]
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[[Category: Arrowsmith, C]]
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[[Category: Bezerra GA]]
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[[Category: Bezerra, G A]]
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[[Category: Bountra C]]
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[[Category: Bountra, C]]
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[[Category: Brandao-Neto J]]
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[[Category: Brandao-Neto, J]]
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[[Category: Brennan P]]
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[[Category: Brennan, P]]
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[[Category: Douangamath A]]
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[[Category: Douangamath, A]]
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[[Category: Edwards A]]
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[[Category: Edwards, A]]
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[[Category: Foster W]]
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[[Category: Foster, W]]
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[[Category: Krojer T]]
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[[Category: Krojer, T]]
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[[Category: Lai K]]
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[[Category: Lai, K]]
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[[Category: Mackinnon SR]]
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[[Category: Mackinnon, S R]]
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[[Category: Yue WW]]
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[[Category: Yue, W W]]
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[[Category: Zhang M]]
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[[Category: Zhang, M]]
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[[Category: Allosteric fragment]]
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[[Category: Binding hotspt]]
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[[Category: Fragment screening]]
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[[Category: Galactokinase 1]]
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[[Category: Galk1]]
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[[Category: Transferase]]

Revision as of 07:05, 7 April 2021

Structure of human galactokinase 1 bound with 2-(4-chlorophenyl)-N-(pyrimidin-2-yl)acetamide

PDB ID 6zgv

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