5wbr: Difference between revisions

Latest revision as of 14:10, 4 October 2023

Structure of human Ketohexokinase complexed with hits from fragment screening

Structural highlights

5wbr is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.58Å
Ligands:	A3Y, CIT, GOL, SO4
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

KHK_HUMAN Defects in KHK are the cause of fructosuria (FRUCT) [MIM:229800. Benign defect of intermediary metabolism.^[1] ^[2]

Function

KHK_HUMAN

Publication Abstract from PubMed

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^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Trinh CH, Asipu A, Bonthron DT, Phillips SE. Structures of alternatively spliced isoforms of human ketohexokinase. Acta Crystallogr D Biol Crystallogr. 2009 Mar;65(Pt 3):201-11. Epub 2009, Feb 20. PMID:19237742 doi:S0907444908041115
↑ Bonthron DT, Brady N, Donaldson IA, Steinmann B. Molecular basis of essential fructosuria: molecular cloning and mutational analysis of human ketohexokinase (fructokinase). Hum Mol Genet. 1994 Sep;3(9):1627-31. PMID:7833921
↑ 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. Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK). J Med Chem. 2017 Sep 11. doi: 10.1021/acs.jmedchem.7b00947. PMID:28853885 doi:https://dx.doi.org/10.1021/acs.jmedchem.7b00947

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OCA

[1] Trinh CH, Asipu A, Bonthron DT, Phillips SE. Structures of alternatively spliced isoforms of human ketohexokinase. Acta Crystallogr D Biol Crystallogr. 2009 Mar;65(Pt 3):201-11. Epub 2009, Feb 20. PMID:19237742 doi:S0907444908041115

[2] Bonthron DT, Brady N, Donaldson IA, Steinmann B. Molecular basis of essential fructosuria: molecular cloning and mutational analysis of human ketohexokinase (fructokinase). Hum Mol Genet. 1994 Sep;3(9):1627-31. PMID:7833921

[3] 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. Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK). J Med Chem. 2017 Sep 11. doi: 10.1021/acs.jmedchem.7b00947. PMID:28853885 doi:https://dx.doi.org/10.1021/acs.jmedchem.7b00947

[1]

[2]

[3]

@@ Line 3: / Line 3: @@
 <StructureSection load='5wbr' size='340' side='right'caption='[[5wbr]], [[Resolution|resolution]] 2.58&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5wbr]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WBR OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5WBR FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5wbr]] 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=5WBR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5WBR FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A3Y:6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-[(3S)-3-(hydroxymethyl)piperidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile'>A3Y</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]] 2.58&#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=A3Y:6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-[(3S)-3-(hydroxymethyl)piperidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile'>A3Y</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://proteopedia.org/fgij/fg.htm?mol=5wbr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wbr OCA], [http://pdbe.org/5wbr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wbr RCSB], [http://www.ebi.ac.uk/pdbsum/5wbr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wbr 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=5wbr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wbr OCA], [https://pdbe.org/5wbr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5wbr RCSB], [https://www.ebi.ac.uk/pdbsum/5wbr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5wbr ProSAT]</span></td></tr>
 </table>
 == 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>
+== Function ==
+[https://www.uniprot.org/uniprot/KHK_HUMAN KHK_HUMAN]
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 26: / Line 28: @@
 __TOC__
 </StructureSection>
-[[Category: Ketohexokinase]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Pandit, J]]
+[[Category: Pandit J]]
-[[Category: Fragment-based drug discovery]]
-[[Category: Sbdd]]
-[[Category: Transferase]]

5wbr: Difference between revisions

Latest revision as of 14:10, 4 October 2023

Structure of human Ketohexokinase complexed with hits from fragment screening

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

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