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| | ==Crystal structure of human muscle L-lactate dehydrogenase in complex with inhibitor 1, 3-{[3-CARBAMOYL-7-(2,4-DIMETHOXYPYRIMIDIN-5-YL)QUINOLIN-4-YL]AMINO}BENZOIC ACID== | | ==Crystal structure of human muscle L-lactate dehydrogenase in complex with inhibitor 1, 3-{[3-CARBAMOYL-7-(2,4-DIMETHOXYPYRIMIDIN-5-YL)QUINOLIN-4-YL]AMINO}BENZOIC ACID== |
| - | <StructureSection load='4qt0' size='340' side='right' caption='[[4qt0]], [[Resolution|resolution]] 3.20Å' scene=''> | + | <StructureSection load='4qt0' size='340' side='right'caption='[[4qt0]], [[Resolution|resolution]] 3.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4qt0]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QT0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4QT0 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4qt0]] 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=4QT0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QT0 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=38Q:3-{[3-CARBAMOYL-7-(2,4-DIMETHOXYPYRIMIDIN-5-YL)QUINOLIN-4-YL]AMINO}BENZOIC+ACID'>38Q</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=38Q:3-{[3-CARBAMOYL-7-(2,4-DIMETHOXYPYRIMIDIN-5-YL)QUINOLIN-4-YL]AMINO}BENZOIC+ACID'>38Q</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4qsm|4qsm]], [[4ojn|4ojn]], [[4okn|4okn]]</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=4qt0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qt0 OCA], [https://pdbe.org/4qt0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qt0 RCSB], [https://www.ebi.ac.uk/pdbsum/4qt0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qt0 ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">LDHA, PIG19 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <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>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4qt0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qt0 OCA], [http://pdbe.org/4qt0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4qt0 RCSB], [http://www.ebi.ac.uk/pdbsum/4qt0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4qt0 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[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> | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4qt0" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4qt0" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Lactate dehydrogenase 3D structures|Lactate dehydrogenase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: L-lactate dehydrogenase]] | + | [[Category: Large Structures]] |
| - | [[Category: Craig, L]] | + | [[Category: Craig L]] |
| - | [[Category: Kolappan, S]] | + | [[Category: Kolappan S]] |
| - | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
| + | |
| - | [[Category: Rossmann fold]]
| + | |
| - | [[Category: Tetramer]]
| + | |
| Structural highlights
Disease
LDHA_HUMAN Defects in LDHA are the cause of glycogen storage disease type 11 (GSD11) [MIM:612933. A metabolic disorder that results in exertional myoglobinuria, pain, cramps and easy fatigue.[1]
Function
LDHA_HUMAN
Publication Abstract from PubMed
Lactate dehydrogenase (LDH) is an essential metabolic enzyme that catalyzes the interconversion of pyruvate and lactate using NADH/NAD(+) as a co-substrate. Many cancer cells exhibit a glycolytic phenotype known as the Warburg effect, in which elevated LDH levels enhance the conversion of glucose to lactate, making LDH an attractive therapeutic target for oncology. Two known inhibitors of the human muscle LDH isoform, LDHA, designated 1 and 2, were selected, and their IC50 values were determined to be 14.4 +/- 3.77 and 2.20 +/- 0.15 microM, respectively. The X-ray crystal structures of LDHA in complex with each inhibitor were determined; both inhibitors bind to a site overlapping with the NADH-binding site. Further, an apo LDHA crystal structure solved in a new space group is reported, as well as a complex with both NADH and the substrate analogue oxalate bound in seven of the eight molecules and an oxalate only bound in the eighth molecule in the asymmetric unit. In this latter structure, a kanamycin molecule is located in the inhibitor-binding site, thereby blocking NADH binding. These structures provide insights into LDHA enzyme mechanism and inhibition and a framework for structure-assisted drug design that may contribute to new cancer therapies.
Structures of lactate dehydrogenase A (LDHA) in apo, ternary and inhibitor-bound forms.,Kolappan S, Shen DL, Mosi R, Sun J, McEachern EJ, Vocadlo DJ, Craig L Acta Crystallogr D Biol Crystallogr. 2015 Feb;71(Pt 2):185-95. doi:, 10.1107/S1399004714024791. Epub 2015 Jan 23. PMID:25664730[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Maekawa M, Sudo K, Kanno T, Li SS. Molecular characterization of genetic mutation in human lactate dehydrogenase-A (M) deficiency. Biochem Biophys Res Commun. 1990 Apr 30;168(2):677-82. PMID:2334430
- ↑ Kolappan S, Shen DL, Mosi R, Sun J, McEachern EJ, Vocadlo DJ, Craig L. Structures of lactate dehydrogenase A (LDHA) in apo, ternary and inhibitor-bound forms. Acta Crystallogr D Biol Crystallogr. 2015 Feb;71(Pt 2):185-95. doi:, 10.1107/S1399004714024791. Epub 2015 Jan 23. PMID:25664730 doi:http://dx.doi.org/10.1107/S1399004714024791
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