4l4r: Difference between revisions
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==Structural Characterisation of the Apo-form of Human Lactate Dehydrogenase M Isozyme== | ==Structural Characterisation of the Apo-form of Human Lactate Dehydrogenase M Isozyme== | ||
<StructureSection load='4l4r' size='340' side='right' caption='[[4l4r]], [[Resolution|resolution]] 2.10Å' scene=''> | <StructureSection load='4l4r' size='340' side='right'caption='[[4l4r]], [[Resolution|resolution]] 2.10Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
[[4l4r]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4L4R OCA]. <br> | <table><tr><td colspan='2'>[[4l4r]] is a 2 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=4L4R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4L4R FirstGlance]. <br> | ||
<b> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1Å</td></tr> | ||
<b> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4l4r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l4r OCA], [https://pdbe.org/4l4r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4l4r RCSB], [https://www.ebi.ac.uk/pdbsum/4l4r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4l4r ProSAT]</span></td></tr> | ||
</table> | |||
== Disease == | == 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 == | == Function == | ||
[https://www.uniprot.org/uniprot/LDHA_HUMAN LDHA_HUMAN] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Lactate dehydrogenase A (LDH-A) is a key enzyme in anaerobic respiration that is predominantly found in skeletal muscle and catalyses the reversible conversion of pyruvate to lactate in the presence of NADH. LDH-A is overexpressed in many tumours and has therefore emerged as an attractive target for anticancer drug discovery. Crystal structures of human LDH-A in the presence of inhibitors have been described, but currently no structures of the apo or binary NADH-bound forms are available for any mammalian LDH-A. Here, the apo structure of human LDH-A was solved at a resolution of 2.1 A in space group P4122. The active-site loop adopts an open conformation and the packing and crystallization conditions suggest that the crystal form is suitable for soaking experiments. The soaking potential was assessed with the cofactor NADH, which yielded a ligand-bound crystal structure in the absence of any inhibitors. The structures show that NADH binding induces small conformational changes in the active-site loop and an adjacent helix. A comparison with other eukaryotic apo LDH structures reveals the conservation of intra-loop interactions. The structures provide novel insight into cofactor binding and provide the foundation for soaking experiments with fragments and inhibitors. | |||
Structural characterization of the apo form and NADH binary complex of human lactate dehydrogenase.,Dempster S, Harper S, Moses JE, Dreveny I Acta Crystallogr D Biol Crystallogr. 2014 May;70(Pt 5):1484-90. doi:, 10.1107/S1399004714005422. Epub 2014 Apr 30. PMID:24816116<ref>PMID:24816116</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4l4r" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Lactate dehydrogenase 3D structures|Lactate dehydrogenase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Dempster S]] | ||
[[Category: Dreveny I]] | |||
[[Category: | [[Category: Harper S]] | ||
[[Category: | [[Category: Moses JE]] | ||
[[Category: | |||
Latest revision as of 19:11, 20 September 2023
Structural Characterisation of the Apo-form of Human Lactate Dehydrogenase M IsozymeStructural Characterisation of the Apo-form of Human Lactate Dehydrogenase M Isozyme
Structural highlights
DiseaseLDHA_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] FunctionPublication Abstract from PubMedLactate dehydrogenase A (LDH-A) is a key enzyme in anaerobic respiration that is predominantly found in skeletal muscle and catalyses the reversible conversion of pyruvate to lactate in the presence of NADH. LDH-A is overexpressed in many tumours and has therefore emerged as an attractive target for anticancer drug discovery. Crystal structures of human LDH-A in the presence of inhibitors have been described, but currently no structures of the apo or binary NADH-bound forms are available for any mammalian LDH-A. Here, the apo structure of human LDH-A was solved at a resolution of 2.1 A in space group P4122. The active-site loop adopts an open conformation and the packing and crystallization conditions suggest that the crystal form is suitable for soaking experiments. The soaking potential was assessed with the cofactor NADH, which yielded a ligand-bound crystal structure in the absence of any inhibitors. The structures show that NADH binding induces small conformational changes in the active-site loop and an adjacent helix. A comparison with other eukaryotic apo LDH structures reveals the conservation of intra-loop interactions. The structures provide novel insight into cofactor binding and provide the foundation for soaking experiments with fragments and inhibitors. Structural characterization of the apo form and NADH binary complex of human lactate dehydrogenase.,Dempster S, Harper S, Moses JE, Dreveny I Acta Crystallogr D Biol Crystallogr. 2014 May;70(Pt 5):1484-90. doi:, 10.1107/S1399004714005422. Epub 2014 Apr 30. PMID:24816116[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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