6ke3: Difference between revisions
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The entry | ==Crystal structure of the alpha bata heterodimer of human IDH3 in complex with NADH== | ||
<StructureSection load='6ke3' size='340' side='right'caption='[[6ke3]], [[Resolution|resolution]] 3.31Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6ke3]] 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=6KE3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6KE3 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAI:1,4-DIHYDRONICOTINAMIDE+ADENINE+DINUCLEOTIDE'>NAI</scene></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IDH3A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), IDH3B ([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/Isocitrate_dehydrogenase_(NAD(+)) Isocitrate dehydrogenase (NAD(+))], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.41 1.1.1.41] </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=6ke3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ke3 OCA], [http://pdbe.org/6ke3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ke3 RCSB], [http://www.ebi.ac.uk/pdbsum/6ke3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ke3 ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[http://www.uniprot.org/uniprot/IDH3B_HUMAN IDH3B_HUMAN]] Retinitis pigmentosa. The disease is caused by mutations affecting the gene represented in this entry. | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/IDH3B_HUMAN IDH3B_HUMAN]] Plays a structural role to facilitate the assembly and ensure the full activity of the enzyme catalyzing the decarboxylation of isocitrate (ICT) into alpha-ketoglutarate. The heterodimer composed of the alpha (IDH3A) and beta (IDH3B) subunits and the heterodimer composed of the alpha (IDH3A) and gamma (IDH3G) subunits, have considerable basal activity but the full activity of the heterotetramer (containing two subunits of IDH3A, one of IDH3B and one of IDH3G) requires the assembly and cooperative function of both heterodimers.<ref>PMID:28139779</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Mammalian mitochondrial NAD-dependent isocitrate dehydrogenase (NAD-IDH) catalyzes the decarboxylation of isocitrate into alpha-ketoglutarate in the tricarboxylic acid cycle. It exists as the alpha2betagamma heterotetramer composed of the alphabeta and alphagamma heterodimers. Different from the alphagamma heterodimer that can be allosterically activated by CIT and ADP, the alphabeta heterodimer cannot be allosterically regulated by the activators; however, the molecular mechanism is unclear. We report here the crystal structures of the alphabeta heterodimer of human NAD-IDH with the alpha subunit in apo form and in Ca(2+)-bound, NAD-bound, and NADH-bound forms. Structural analyses and comparisons reveal that the alphabeta heterodimer has a similar yet more compact overall structure compared with the alphagamma heterodimer and contains a pseudo-allosteric site that is structurally different from the allosteric site. In particular, the beta3-alpha3 and beta12-alpha8 loops of the beta subunit at the pseudo-allosteric site adopt significantly different conformations from those of the gamma subunit at the allosteric site and hence impede the binding of the activators, explaining why the alphabeta heterodimer cannot be allosterically regulated by the activators. The structural data also show that NADH can compete with NAD to bind to the active site and inhibits the activity of the alphabeta heterodimer. These findings together with the biochemical data reveal the molecular basis for the function of the alphabeta heterodimer of human NAD-IDH. | |||
Molecular basis for the function of the alphabeta heterodimer of human NAD-dependent isocitrate dehydrogenase.,Sun P, Ma T, Zhang T, Zhu H, Zhang J, Liu Y, Ding J J Biol Chem. 2019 Nov 1;294(44):16214-16227. doi: 10.1074/jbc.RA119.010099. Epub , 2019 Sep 12. PMID:31515270<ref>PMID:31515270</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Ding, J | <div class="pdbe-citations 6ke3" style="background-color:#fffaf0;"></div> | ||
[[Category: Sun, P | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Ding, J]] | |||
[[Category: Sun, P]] | |||
[[Category: Nad dependent isocitrate dehydrogenase]] | |||
[[Category: Oxidoreductase]] | |||
Revision as of 15:58, 25 December 2019
Crystal structure of the alpha bata heterodimer of human IDH3 in complex with NADHCrystal structure of the alpha bata heterodimer of human IDH3 in complex with NADH
Structural highlights
Disease[IDH3B_HUMAN] Retinitis pigmentosa. The disease is caused by mutations affecting the gene represented in this entry. Function[IDH3B_HUMAN] Plays a structural role to facilitate the assembly and ensure the full activity of the enzyme catalyzing the decarboxylation of isocitrate (ICT) into alpha-ketoglutarate. The heterodimer composed of the alpha (IDH3A) and beta (IDH3B) subunits and the heterodimer composed of the alpha (IDH3A) and gamma (IDH3G) subunits, have considerable basal activity but the full activity of the heterotetramer (containing two subunits of IDH3A, one of IDH3B and one of IDH3G) requires the assembly and cooperative function of both heterodimers.[1] Publication Abstract from PubMedMammalian mitochondrial NAD-dependent isocitrate dehydrogenase (NAD-IDH) catalyzes the decarboxylation of isocitrate into alpha-ketoglutarate in the tricarboxylic acid cycle. It exists as the alpha2betagamma heterotetramer composed of the alphabeta and alphagamma heterodimers. Different from the alphagamma heterodimer that can be allosterically activated by CIT and ADP, the alphabeta heterodimer cannot be allosterically regulated by the activators; however, the molecular mechanism is unclear. We report here the crystal structures of the alphabeta heterodimer of human NAD-IDH with the alpha subunit in apo form and in Ca(2+)-bound, NAD-bound, and NADH-bound forms. Structural analyses and comparisons reveal that the alphabeta heterodimer has a similar yet more compact overall structure compared with the alphagamma heterodimer and contains a pseudo-allosteric site that is structurally different from the allosteric site. In particular, the beta3-alpha3 and beta12-alpha8 loops of the beta subunit at the pseudo-allosteric site adopt significantly different conformations from those of the gamma subunit at the allosteric site and hence impede the binding of the activators, explaining why the alphabeta heterodimer cannot be allosterically regulated by the activators. The structural data also show that NADH can compete with NAD to bind to the active site and inhibits the activity of the alphabeta heterodimer. These findings together with the biochemical data reveal the molecular basis for the function of the alphabeta heterodimer of human NAD-IDH. Molecular basis for the function of the alphabeta heterodimer of human NAD-dependent isocitrate dehydrogenase.,Sun P, Ma T, Zhang T, Zhu H, Zhang J, Liu Y, Ding J J Biol Chem. 2019 Nov 1;294(44):16214-16227. doi: 10.1074/jbc.RA119.010099. Epub , 2019 Sep 12. PMID:31515270[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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