5sci - Revision history

OCA at 10:00, 22 May 2024

2024-05-22T10:00:40Z

← Older revision		Revision as of 10:00, 22 May 2024
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	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/KPYR_HUMAN KPYR_HUMAN] Plays a key role in glycolysis (By similarity).		[https://www.uniprot.org/uniprot/KPYR_HUMAN KPYR_HUMAN] Plays a key role in glycolysis (By similarity).
			<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 5sci" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 15:30, 6 March 2024

2024-03-06T15:30:20Z

← Older revision		Revision as of 15:30, 6 March 2024
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	<StructureSection load='5sci' size='340' side='right'caption='[[5sci]], [[Resolution\|resolution]] 2.15Å' scene=''>		<StructureSection load='5sci' size='340' side='right'caption='[[5sci]], [[Resolution\|resolution]] 2.15Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[5sci]] is a 8 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5SCI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5SCI FirstGlance]. <br>		<table><tr><td colspan='2'>[[5sci]] is a 8 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=5SCI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5SCI FirstGlance]. <br>
	</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=I9F:dimethyl+(2R)-2-hydroxy-2-{2-[4-(3-hydroxy-9,10-dioxo-9,10-dihydroanthracene-2-sulfonyl)piperazin-1-yl]-2-oxoethyl}butanedioate'>I9F</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>~~		</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.155Å</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='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=I9F:dimethyl+(2R)-2-hydroxy-2-{2-[4-(3-hydroxy-9,10-dioxo-9,10-dihydroanthracene-2-sulfonyl)piperazin-1-yl]-2-oxoethyl}butanedioate'>I9F</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5sci FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5sci OCA], [https://pdbe.org/5sci PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5sci RCSB], [https://www.ebi.ac.uk/pdbsum/5sci PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5sci 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=5sci FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5sci OCA], [https://pdbe.org/5sci PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5sci RCSB], [https://www.ebi.ac.uk/pdbsum/5sci PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5sci ProSAT]</span></td></tr>
	</table>		</table>
	~~<div style="background-color:#fffaf0;">~~		== Disease ==
	== ~~Publication Abstract from PubMed~~ ==		[https://www.uniprot.org/uniprot/KPYR_HUMAN KPYR_HUMAN] Defects in PKLR are the cause of pyruvate kinase hyperactivity (PKHYP) [MIM:[https://omim.org/entry/102900 102900]; also known as high red cell ATP syndrome. This autosomal dominant phenotype is characterized by increase of red blood cell ATP.<ref>PMID:9090535</ref> Defects in PKLR are the cause of pyruvate kinase deficiency of red cells (PKRD) [MIM:[https://omim.org/entry/266200 266200]. A frequent cause of hereditary non-spherocytic hemolytic anemia. Clinically, pyruvate kinase-deficient patients suffer from a highly variable degree of chronic hemolysis, ranging from severe neonatal jaundice and fatal anemia at birth, severe transfusion-dependent chronic hemolysis, moderate hemolysis with exacerbation during infection, to a fully compensated hemolysis without apparent anemia.
	~~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~~.		== Function ==
			[https://www.uniprot.org/uniprot/KPYR_HUMAN KPYR_HUMAN] Plays a key role in glycolysis (By similarity).

	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>		==See Also==
			*[[Pyruvate kinase 3D structures\|Pyruvate kinase 3D structures]]
	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~
	~~</div>~~
	~~<div class~~=~~"pdbe-citations 5sci" style~~=~~"background-color:#fffaf0;"></div>~~
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
			[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	~~[[Category: Pyruvate kinase]]~~		[[Category: Brear P]]
	[[Category: Brear, P]]		[[Category: Foller A]]
	[[Category: Foller, A]]		[[Category: Grotli M]]
	[[Category: Grotli, M]]		[[Category: Hyvonen M]]
	[[Category: Hyvonen, M]]		[[Category: Lulla A]]
	[[Category: Lulla, A]]		[[Category: Nain-Perez A]]
	[[Category: Nain-Perez, A]]
	~~[[Category: Active site]]~~
	~~[[Category: Inhibition]]~~
	~~[[Category: Transferase]]~~
	~~[[Category: Transferase-transferase inhibitor complex~~]]

OCA at 10:57, 30 March 2022

2022-03-30T10:57:33Z

← Older revision		Revision as of 10:57, 30 March 2022
Line 1:		Line 1:

	==Structure of liver pyruvate kinase in complex with anthraquinone derivative 105==		==Structure of liver pyruvate kinase in complex with anthraquinone derivative 105==
	<StructureSection load='5sci' size='340' side='right'caption='[[5sci]]' scene=''>		<StructureSection load='5sci' size='340' side='right'caption='[[5sci]], [[Resolution\|resolution]] 2.15Å' 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=5SCI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5SCI FirstGlance]. <br>		<table><tr><td colspan='2'>[[5sci]] is a 8 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5SCI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5SCI 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=5sci FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5sci OCA], [https://pdbe.org/5sci PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5sci RCSB], [https://www.ebi.ac.uk/pdbsum/5sci PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5sci 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=I9F:dimethyl+(2R)-2-hydroxy-2-{2-[4-(3-hydroxy-9,10-dioxo-9,10-dihydroanthracene-2-sulfonyl)piperazin-1-yl]-2-oxoethyl}butanedioate'>I9F</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=5sci FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5sci OCA], [https://pdbe.org/5sci PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5sci RCSB], [https://www.ebi.ac.uk/pdbsum/5sci PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5sci 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 5sci" 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]]

OCA at 06:10, 16 March 2022

2022-03-16T06:10:48Z

← Older revision		Revision as of 06:10, 16 March 2022
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	~~'''Unreleased structure'''~~

	~~The entry~~ 5sci is ~~ON HOLD~~		==Structure of liver pyruvate kinase in complex with anthraquinone derivative 105==
			<StructureSection load='5sci' size='340' side='right'caption='[[5sci]]' scene=''>
	~~Authors~~: ~~Lulla~~, A.~~, Foller, A~~.~~, Nain~~-~~Perez~~, A., ~~Grotli~~, M., ~~Brear, P~~.~~, Hyvonen, M~~.		== Structural highlights ==
			<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5SCI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5SCI FirstGlance]. <br>
	~~Description: Structure of liver pyruvate kinase in complex with anthraquinone derivative 105~~		</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=5sci FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5sci OCA], [https://pdbe.org/5sci PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5sci RCSB], [https://www.ebi.ac.uk/pdbsum/5sci PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5sci ProSAT]</span></td></tr>
	[[Category: ~~Unreleased~~ Structures]]		</table>
	[[Category: Brear, P]]		__TOC__
	[[Category: Foller, A]]		</StructureSection>
	[[Category: ~~Hyvonen,~~ M]]		[[Category: Large Structures]]
	[[Category: ~~Lulla, A~~]]		[[Category: Brear P]]
	[[Category: ~~Grotli, M~~]]		[[Category: Foller A]]
	[[Category: Nain-Perez, A]]		[[Category: Grotli M]]
			[[Category: Hyvonen M]]
			[[Category: Lulla A]]
			[[Category: Nain-Perez A]]

OCA at 05:18, 2 February 2022

2022-02-02T05:18:40Z

← Older revision		Revision as of 05:18, 2 February 2022
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	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 5sci is ON HOLD ~~until sometime in the future~~		The entry 5sci is ON HOLD

	Authors: Lulla, A., Foller, A., Nain-Perez, A., Grotli, M., Brear, P., Hyvonen, M.		Authors: Lulla, A., Foller, A., Nain-Perez, A., Grotli, M., Brear, P., Hyvonen, M.

OCA at 13:48, 22 December 2021

2021-12-22T13:48:28Z

← Older revision		Revision as of 13:48, 22 December 2021
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	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 5sci is ON HOLD		The entry 5sci is ON HOLD until sometime in the future

	Authors: Lulla, A., Foller, A., Nain-Perez, A., Grotli, M., Brear, P., Hyvonen, M.		Authors: Lulla, A., Foller, A., Nain-Perez, A., Grotli, M., Brear, P., Hyvonen, M.

OCA: Protected "5sci" [edit=sysop:move=sysop]

2021-12-08T08:23:55Z

Protected "5sci" [edit=sysop:move=sysop]

← Older revision	Revision as of 08:23, 8 December 2021
(No difference)

OCA: New page: '''Unreleased structure''' The entry 5sci is ON HOLD Authors: Lulla, A., Foller, A., Nain-Perez, A., Grotli, M., Brear, P., Hyvonen, M. Description: Structure of liver pyruvate kinase ...

2021-12-08T08:23:54Z

New page: '''Unreleased structure''' The entry 5sci is ON HOLD Authors: Lulla, A., Foller, A., Nain-Perez, A., Grotli, M., Brear, P., Hyvonen, M. Description: Structure of liver pyruvate kinase ...

New page

'''Unreleased structure'''

The entry 5sci is ON HOLD

Authors: Lulla, A., Foller, A., Nain-Perez, A., Grotli, M., Brear, P., Hyvonen, M.

Description: Structure of liver pyruvate kinase in complex with anthraquinone derivative 105
[[Category: Unreleased Structures]]
[[Category: Brear, P]]
[[Category: Foller, A]]
[[Category: Hyvonen, M]]
[[Category: Lulla, A]]
[[Category: Grotli, M]]
[[Category: Nain-Perez, A]]