View source for 4qo8


==Lactate Dehydrogenase A in complex with substituted 3-Hydroxy-2-mercaptocyclohex-2-enone compound 104==
<StructureSection load='4qo8' size='340' side='right'caption='[[4qo8]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4qo8]] 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=4QO8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QO8 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.001&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=36U:(5S)-2-[(2-CHLOROPHENYL)SULFANYL]-5-(2,6-DICHLOROPHENYL)-3-HYDROXYCYCLOHEX-2-EN-1-ONE'>36U</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=LAC:LACTIC+ACID'>LAC</scene>, <scene name='pdbligand=NAI:1,4-DIHYDRONICOTINAMIDE+ADENINE+DINUCLEOTIDE'>NAI</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'>[https://proteopedia.org/fgij/fg.htm?mol=4qo8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qo8 OCA], [https://pdbe.org/4qo8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qo8 RCSB], [https://www.ebi.ac.uk/pdbsum/4qo8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qo8 ProSAT]</span></td></tr>
</table>
== Disease ==
[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> 
== Function ==
[https://www.uniprot.org/uniprot/LDHA_HUMAN LDHA_HUMAN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
A novel class of 3-hydroxy-2-mercaptocyclohex-2-enone-containing inhibitors of human lactate dehydrogenase (LDH) was identified through a high-throughput screening approach. Biochemical and surface plasmon resonance experiments performed with a screening hit (LDHA IC50=1.7muM) indicated that the compound specifically associated with human LDHA in a manner that required simultaneous binding of the NADH co-factor. Structural variation of this screening hit resulted in significant improvements in LDHA biochemical inhibition activity (best IC50=0.18muM). Two crystal structures of optimized compounds bound to human LDHA were obtained and explained many of the observed structure-activity relationships. In addition, an optimized inhibitor exhibited good pharmacokinetic properties after oral administration to rats (F=45%).

Identification of substituted 3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase.,Dragovich PS, Fauber BP, Boggs J, Chen J, Corson LB, Ding CZ, Eigenbrot C, Ge H, Giannetti AM, Hunsaker T, Labadie S, Li C, Liu Y, Liu Y, Ma S, Malek S, Peterson D, Pitts KE, Purkey HE, Robarge K, Salphati L, Sideris S, Ultsch M, VanderPorten E, Wang J, Wei B, Xu Q, Yen I, Yue Q, Zhang H, Zhang X, Zhou A Bioorg Med Chem Lett. 2014 Aug 15;24(16):3764-71. doi:, 10.1016/j.bmcl.2014.06.076. Epub 2014 Jul 1. PMID:25037916<ref>PMID:25037916</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4qo8" style="background-color:#fffaf0;"></div>

==See Also==
*[[Lactate dehydrogenase 3D structures|Lactate dehydrogenase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Eigenbrot C]]
[[Category: Ultsch M]]