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==Structure of human Ketohexokinase complexed with hits from fragment screening==
==Structure of human Ketohexokinase complexed with hits from fragment screening==
<StructureSection load='5wbo' size='340' side='right' caption='[[5wbo]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
<StructureSection load='5wbo' size='340' side='right'caption='[[5wbo]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5wbo]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WBO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WBO FirstGlance]. <br>
<table><tr><td colspan='2'>[[5wbo]] is a 2 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=5WBO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5WBO FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=A1Y:4,6-dimethyl-2-(morpholin-4-yl)pyridine-3-carbonitrile'>A1Y</scene>, <scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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]] 2.25&#8491;</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Ketohexokinase Ketohexokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.3 2.7.1.3] </span></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1Y:4,6-dimethyl-2-(morpholin-4-yl)pyridine-3-carbonitrile'>A1Y</scene>, <scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5wbo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wbo OCA], [http://pdbe.org/5wbo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wbo RCSB], [http://www.ebi.ac.uk/pdbsum/5wbo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wbo ProSAT]</span></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=5wbo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wbo OCA], [https://pdbe.org/5wbo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5wbo RCSB], [https://www.ebi.ac.uk/pdbsum/5wbo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5wbo ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/KHK_HUMAN KHK_HUMAN]] Defects in KHK are the cause of fructosuria (FRUCT) [MIM:[http://omim.org/entry/229800 229800]]. Benign defect of intermediary metabolism.<ref>PMID:19237742</ref> <ref>PMID:7833921</ref>
[https://www.uniprot.org/uniprot/KHK_HUMAN KHK_HUMAN] Defects in KHK are the cause of fructosuria (FRUCT) [MIM:[https://omim.org/entry/229800 229800]. Benign defect of intermediary metabolism.<ref>PMID:19237742</ref> <ref>PMID:7833921</ref>  
<div style="background-color:#fffaf0;">
== Function ==
== Publication Abstract from PubMed ==
[https://www.uniprot.org/uniprot/KHK_HUMAN KHK_HUMAN]
Increased fructose consumption and its subsequent metabolism have been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin resistance in humans. Since ketohexokinase (KHK) is the principal enzyme responsible for fructose metabolism, identification of a selective KHK inhibitor may help to further elucidate the effect of KHK inhibition on these metabolic disorders. Until now, studies on KHK inhibition with small molecules have been limited due to the lack of viable in vivo pharmacological tools. Herein we report the discovery of 12, a selective KHK inhibitor with potency and properties suitable for evaluating KHK inhibition in rat models. Key structural features interacting with KHK were discovered through fragment-based screening and subsequent optimization using structure-based drug design, and parallel medicinal chemistry led to the identification of pyridine 12.


Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK).,Huard K, Ahn K, Amor P, Beebe DA, Borzilleri KA, Chrunyk BA, Coffey SB, Cong Y, Conn EL, Culp JS, Dowling MS, Gorgoglione MF, Gutierrez JA, Knafels JD, Lachapelle EA, Pandit J, Parris KD, Perez S, Pfefferkorn JA, Price DA, Raymer B, Ross TT, Shavnya A, Smith AC, Subashi TA, Tesz GJ, Thuma BA, Tu M, Weaver JD, Weng Y, Withka JM, Xing G, Magee TV J Med Chem. 2017 Sep 11. doi: 10.1021/acs.jmedchem.7b00947. PMID:28853885<ref>PMID:28853885</ref>
==See Also==
 
*[[Ketohexokinase|Ketohexokinase]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5wbo" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Ketohexokinase]]
[[Category: Homo sapiens]]
[[Category: Pandit, J]]
[[Category: Large Structures]]
[[Category: Fragment-based drug discovery]]
[[Category: Pandit J]]
[[Category: Sbdd]]
[[Category: Transferase]]

Latest revision as of 14:15, 13 March 2024

Structure of human Ketohexokinase complexed with hits from fragment screening

5wbo, resolution 2.25Å

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