5w8l

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Current revision (14:14, 13 March 2024) (edit) (undo)
 
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<StructureSection load='5w8l' size='340' side='right'caption='[[5w8l]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
<StructureSection load='5w8l' size='340' side='right'caption='[[5w8l]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5w8l]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5W8L OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5W8L FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5w8l]] is a 4 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=5W8L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5W8L FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9YA:2-{3-([1,1-biphenyl]-3-yl)-5-(cyclopropylmethyl)-4-[(4-sulfamoylphenyl)methyl]-1H-pyrazol-1-yl}-1,3-thiazole-4-carboxylic+acid'>9YA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAI:1,4-DIHYDRONICOTINAMIDE+ADENINE+DINUCLEOTIDE'>NAI</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.95&#8491;</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/L-lactate_dehydrogenase L-lactate dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.27 1.1.1.27] </span></td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9YA:2-{3-([1,1-biphenyl]-3-yl)-5-(cyclopropylmethyl)-4-[(4-sulfamoylphenyl)methyl]-1H-pyrazol-1-yl}-1,3-thiazole-4-carboxylic+acid'>9YA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAI:1,4-DIHYDRONICOTINAMIDE+ADENINE+DINUCLEOTIDE'>NAI</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5w8l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w8l OCA], [http://pdbe.org/5w8l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5w8l RCSB], [http://www.ebi.ac.uk/pdbsum/5w8l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5w8l ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5w8l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w8l OCA], [https://pdbe.org/5w8l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5w8l RCSB], [https://www.ebi.ac.uk/pdbsum/5w8l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5w8l ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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[[http://www.uniprot.org/uniprot/LDHA_HUMAN LDHA_HUMAN]] Defects in LDHA are the cause of glycogen storage disease type 11 (GSD11) [MIM:[http://omim.org/entry/612933 612933]]. A metabolic disorder that results in exertional myoglobinuria, pain, cramps and easy fatigue.<ref>PMID:2334430</ref>
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[https://www.uniprot.org/uniprot/LDHA_HUMAN LDHA_HUMAN] Defects in LDHA are the cause of glycogen storage disease type 11 (GSD11) [MIM:[https://omim.org/entry/612933 612933]. A metabolic disorder that results in exertional myoglobinuria, pain, cramps and easy fatigue.<ref>PMID:2334430</ref>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/LDHA_HUMAN LDHA_HUMAN]
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We report the discovery and medicinal chemistry optimization of a novel series of pyrazole-based inhibitors of human lactate dehydrogenase (LDH). Utilization of a quantitative high-throughput screening paradigm facilitated hit identification, while structure-based design and multiparameter optimization enabled the development of compounds with potent enzymatic and cell-based inhibition of LDH enzymatic activity. Lead compounds such as 63 exhibit low nM inhibition of both LDHA and LDHB, submicromolar inhibition of lactate production, and inhibition of glycolysis in MiaPaCa2 pancreatic cancer and A673 sarcoma cells. Moreover, robust target engagement of LDHA by lead compounds was demonstrated using the cellular thermal shift assay (CETSA), and drug-target residence time was determined via SPR. Analysis of these data suggests that drug-target residence time (off-rate) may be an important attribute to consider for obtaining potent cell-based inhibition of this cancer metabolism target.
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Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH).,Rai G, Brimacombe KR, Mott BT, Urban DJ, Hu X, Yang SM, Lee TD, Cheff DM, Kouznetsova J, Benavides GA, Pohida K, Kuenstner EJ, Luci DK, Lukacs CM, Davies DR, Dranow DM, Zhu H, Sulikowski G, Moore WJ, Stott GM, Flint AJ, Hall MD, Darley-Usmar VM, Neckers LM, Dang CV, Waterson AG, Simeonov A, Jadhav A, Maloney DJ J Med Chem. 2017 Nov 22;60(22):9184-9204. doi: 10.1021/acs.jmedchem.7b00941. Epub, 2017 Nov 9. PMID:29120638<ref>PMID:29120638</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 5w8l" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: L-lactate dehydrogenase]]
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Davies, D R]]
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[[Category: Davies DR]]
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[[Category: Dranow, D M]]
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[[Category: Dranow DM]]
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[[Category: Oxidoreductase]]
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[[Category: Oxidoreductase inhibitor]]
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Current revision

Crystal Structure of Lactate Dehydrogenase A in complex with inhibitor compound 59 and NADH

PDB ID 5w8l

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