5wbq: Difference between revisions
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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='5wbq' size='340' side='right' caption='[[5wbq]], [[Resolution|resolution]] 2.40Å' scene=''> | <StructureSection load='5wbq' size='340' side='right'caption='[[5wbq]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5wbq]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WBQ OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[5wbq]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WBQ OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5WBQ FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=A3J:2-ethyl-7-[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile'>A3J</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A3J:2-ethyl-7-[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile'>A3J</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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='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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http:// | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5wbq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wbq OCA], [http://pdbe.org/5wbq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wbq RCSB], [http://www.ebi.ac.uk/pdbsum/5wbq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wbq ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
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</div> | </div> | ||
<div class="pdbe-citations 5wbq" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5wbq" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Ketohexokinase|Ketohexokinase]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Ketohexokinase]] | [[Category: Ketohexokinase]] | ||
[[Category: Large Structures]] | |||
[[Category: Pandit, J]] | [[Category: Pandit, J]] | ||
[[Category: Fragment-based drug discovery]] | [[Category: Fragment-based drug discovery]] | ||
[[Category: Sbdd]] | [[Category: Sbdd]] | ||
[[Category: Transferase]] | [[Category: Transferase]] | ||
Revision as of 11:50, 30 September 2020
Structure of human Ketohexokinase complexed with hits from fragment screeningStructure of human Ketohexokinase complexed with hits from fragment screening
Structural highlights
Disease[KHK_HUMAN] Defects in KHK are the cause of fructosuria (FRUCT) [MIM:229800]. Benign defect of intermediary metabolism.[1] [2] Publication Abstract from PubMedIncreased 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[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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