5sdt: Difference between revisions
Jump to navigation
Jump to search
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Structure of liver pyruvate kinase in complex with anthraquinone derivative 15== | ==Structure of liver pyruvate kinase in complex with anthraquinone derivative 15== | ||
<StructureSection load='5sdt' size='340' side='right'caption='[[5sdt]]' scene=''> | <StructureSection load='5sdt' size='340' side='right'caption='[[5sdt]], [[Resolution|resolution]] 1.94Å' 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=5SDT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5SDT FirstGlance]. <br> | <table><tr><td colspan='2'>[[5sdt]] is a 8 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5SDT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5SDT 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=5sdt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5sdt OCA], [https://pdbe.org/5sdt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5sdt RCSB], [https://www.ebi.ac.uk/pdbsum/5sdt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5sdt ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FBP:BETA-FRUCTOSE-1,6-DIPHOSPHATE'>FBP</scene>, <scene name='pdbligand=I9Q:N-(3,4-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-sulfonyl)-beta-alanine'>I9Q</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=OXL:OXALATE+ION'>OXL</scene></td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Pyruvate_kinase Pyruvate kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.40 2.7.1.40] </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=5sdt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5sdt OCA], [https://pdbe.org/5sdt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5sdt RCSB], [https://www.ebi.ac.uk/pdbsum/5sdt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5sdt ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Liver pyruvate kinase (PKL) is a major regulator of metabolic flux and ATP production during liver cell glycolysis and is considered a potential drug target for the treatment of non-alcoholic fatty liver disease (NAFLD). In this study, we report the first ADP-competitive PKL inhibitors and identify several starting points for the further optimization of these inhibitors. Modeling and structural biology guided the optimization of a PKL-specific anthraquinone-based compound. A structure-activity relationship study of 47 novel synthetic derivatives revealed PKL inhibitors with half-maximal inhibitory concentration (IC50) values in the 200 nM range. Despite the difficulty involved in studying a binding site as exposed as the ADP site, these derivatives feature expanded structural diversity and chemical spaces that may be used to improve their inhibitory activities against PKL. The obtained results expand the knowledge of the structural requirements for interactions with the ADP-binding site of PKL. | |||
Anthraquinone derivatives as ADP-competitive inhibitors of liver pyruvate kinase.,Nain-Perez A, Foller Fuchtbauer A, Haversen L, Lulla A, Gao C, Matic J, Monjas L, Rodriguez A, Brear P, Kim W, Hyvonen M, Boren J, Mardinoglu A, Uhlen M, Grotli M Eur J Med Chem. 2022 Mar 8;234:114270. doi: 10.1016/j.ejmech.2022.114270. PMID:35290845<ref>PMID:35290845</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5sdt" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Brear P]] | [[Category: Pyruvate kinase]] | ||
[[Category: Foller A]] | [[Category: Brear, P]] | ||
[[Category: Grotli M]] | [[Category: Foller, A]] | ||
[[Category: Hyvonen M]] | [[Category: Grotli, M]] | ||
[[Category: Lulla A]] | [[Category: Hyvonen, M]] | ||
[[Category: Nain-Perez A]] | [[Category: Lulla, A]] | ||
[[Category: Nain-Perez, A]] | |||
[[Category: Active site]] | |||
[[Category: Inhibition]] | |||
[[Category: Transferase]] | |||
[[Category: Transferase-transferase inhibitor complex]] | |||
Revision as of 13:57, 30 March 2022
Structure of liver pyruvate kinase in complex with anthraquinone derivative 15Structure of liver pyruvate kinase in complex with anthraquinone derivative 15
Structural highlights
Publication Abstract from PubMedLiver pyruvate kinase (PKL) is a major regulator of metabolic flux and ATP production during liver cell glycolysis and is considered a potential drug target for the treatment of non-alcoholic fatty liver disease (NAFLD). In this study, we report the first ADP-competitive PKL inhibitors and identify several starting points for the further optimization of these inhibitors. Modeling and structural biology guided the optimization of a PKL-specific anthraquinone-based compound. A structure-activity relationship study of 47 novel synthetic derivatives revealed PKL inhibitors with half-maximal inhibitory concentration (IC50) values in the 200 nM range. Despite the difficulty involved in studying a binding site as exposed as the ADP site, these derivatives feature expanded structural diversity and chemical spaces that may be used to improve their inhibitory activities against PKL. The obtained results expand the knowledge of the structural requirements for interactions with the ADP-binding site of PKL. Anthraquinone derivatives as ADP-competitive inhibitors of liver pyruvate kinase.,Nain-Perez A, Foller Fuchtbauer A, Haversen L, Lulla A, Gao C, Matic J, Monjas L, Rodriguez A, Brear P, Kim W, Hyvonen M, Boren J, Mardinoglu A, Uhlen M, Grotli M Eur J Med Chem. 2022 Mar 8;234:114270. doi: 10.1016/j.ejmech.2022.114270. PMID:35290845[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||||