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| | ==The crystal structure of the subunit binding of human dihydrolipoamide transacylase (E2b) bound to human dihydrolipoamide dehydrogenase (E3)== | | ==The crystal structure of the subunit binding of human dihydrolipoamide transacylase (E2b) bound to human dihydrolipoamide dehydrogenase (E3)== |
| | <StructureSection load='3rnm' size='340' side='right' caption='[[3rnm]], [[Resolution|resolution]] 2.40Å' scene=''> | | <StructureSection load='3rnm' size='340' side='right' caption='[[3rnm]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3rnm]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3RNM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3RNM FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3rnm]] is a 6 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=3RNM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3RNM FirstGlance]. <br> |
| | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=NHE:2-[N-CYCLOHEXYLAMINO]ETHANE+SULFONIC+ACID'>NHE</scene></td></tr> | | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=NHE:2-[N-CYCLOHEXYLAMINO]ETHANE+SULFONIC+ACID'>NHE</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DLD, GCSL, LAD, PHE3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]), DBT, BCATE2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DLD, GCSL, LAD, PHE3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), DBT, BCATE2 ([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/Dihydrolipoyl_dehydrogenase Dihydrolipoyl dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.8.1.4 1.8.1.4] </span></td></tr> | | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydrolipoyl_dehydrogenase Dihydrolipoyl dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.8.1.4 1.8.1.4] </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=3rnm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rnm OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3rnm RCSB], [http://www.ebi.ac.uk/pdbsum/3rnm PDBsum]</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=3rnm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rnm OCA], [http://pdbe.org/3rnm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3rnm RCSB], [http://www.ebi.ac.uk/pdbsum/3rnm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3rnm ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 3rnm" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Dihydrolipoyl dehydrogenase]] | | [[Category: Dihydrolipoyl dehydrogenase]] |
| - | [[Category: Homo sapiens]] | + | [[Category: Human]] |
| | [[Category: Brautigam, C A]] | | [[Category: Brautigam, C A]] |
| | [[Category: Chuang, D T]] | | [[Category: Chuang, D T]] |
| Structural highlights
3rnm is a 6 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , |
| Gene: | DLD, GCSL, LAD, PHE3 (HUMAN), DBT, BCATE2 (HUMAN) |
| Activity: | Dihydrolipoyl dehydrogenase, with EC number 1.8.1.4 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[DLDH_HUMAN] Note=Defects in DLD are involved in the development of congenital infantile lactic acidosis. Defects in DLD are a cause of maple syrup urine disease (MSUD) [MIM:248600]. MSUD is characterized by mental and physical retardation, feeding problems and a maple syrup odor to the urine. The keto acids of the branched-chain amino acids are present in the urine, resulting from a block in oxidative decarboxylation. [ODB2_HUMAN] Defects in DBT are the cause of maple syrup urine disease type 2 (MSUD2) [MIM:248600]. MSUD is an autosomal recessive disorder characterized by mental and physical retardation, feeding problems, and a maple syrup odor to the urine.[1] [2]
Function
[DLDH_HUMAN] Lipoamide dehydrogenase is a component of the glycine cleavage system as well as of the alpha-ketoacid dehydrogenase complexes. Involved in the hyperactivation of spermatazoa during capacitation and in the spermatazoal acrosome reaction. [ODB2_HUMAN] The branched-chain alpha-keto dehydrogenase complex catalyzes the overall conversion of alpha-keto acids to acyl-CoA and CO(2). It contains multiple copies of three enzymatic components: branched-chain alpha-keto acid decarboxylase (E1), lipoamide acyltransferase (E2) and lipoamide dehydrogenase (E3).
Publication Abstract from PubMed
The purified mammalian branched-chain alpha-ketoacid dehydrogenase complex (BCKDC), which catalyzes the oxidative decarboxylation of branched-chain alpha-keto acids, is essentially devoid of the constituent dihydrolipoamide dehydrogenase component (E3). The absence of E3 is associated with the low affinity of the subunit-binding domain of human BCKDC (hSBDb) for hE3. In this work, sequence alignments of hSBDb with the E3-binding domain (E3BD) of the mammalian pyruvate dehydrogenase complex show that hSBDb has an arginine at position 118, where E3BD features an asparagine. Substitution of Arg-118 with an asparagine increases the binding affinity of the R118N hSBDb variant (designated hSBDb*) for hE3 by nearly 2 orders of magnitude. The enthalpy of the binding reaction changes from endothermic with the wild-type hSBDb to exothermic with the hSBDb* variant. This higher affinity interaction allowed the determination of the crystal structure of the hE3/hSBDb* complex to 2.4-A resolution. The structure showed that the presence of Arg-118 poses a unique, possibly steric and/or electrostatic incompatibility that could impede E3 interactions with the wild-type hSBDb. Compared with the E3/E3BD structure, the hE3/hSBDb* structure has a smaller interfacial area. Solution NMR data corroborated the interactions of hE3 with Arg-118 and Asn-118 in wild-type hSBDb and mutant hSBDb*, respectively. The NMR results also showed that the interface between hSBDb and hE3 does not change significantly from hSBDb to hSBDb*. Taken together, our results represent a starting point for explaining the long standing enigma that the E2b core of the BCKDC binds E3 far more weakly relative to other alpha-ketoacid dehydrogenase complexes.
Structural and Thermodynamic Basis for Weak Interactions between Dihydrolipoamide Dehydrogenase and Subunit-binding Domain of the Branched-chain {alpha}-Ketoacid Dehydrogenase Complex.,Brautigam CA, Wynn RM, Chuang JL, Naik MT, Young BB, Huang TH, Chuang DT J Biol Chem. 2011 Jul 1;286(26):23476-88. Epub 2011 May 3. PMID:21543315[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Fisher CW, Lau KS, Fisher CR, Wynn RM, Cox RP, Chuang DT. A 17-bp insertion and a Phe215----Cys missense mutation in the dihydrolipoyl transacylase (E2) mRNA from a thiamine-responsive maple syrup urine disease patient WG-34. Biochem Biophys Res Commun. 1991 Jan 31;174(2):804-9. PMID:1847055
- ↑ Tsuruta M, Mitsubuchi H, Mardy S, Miura Y, Hayashida Y, Kinugasa A, Ishitsu T, Matsuda I, Indo Y. Molecular basis of intermittent maple syrup urine disease: novel mutations in the E2 gene of the branched-chain alpha-keto acid dehydrogenase complex. J Hum Genet. 1998;43(2):91-100. PMID:9621512 doi:10.1007/s100380050047
- ↑ Brautigam CA, Wynn RM, Chuang JL, Naik MT, Young BB, Huang TH, Chuang DT. Structural and Thermodynamic Basis for Weak Interactions between Dihydrolipoamide Dehydrogenase and Subunit-binding Domain of the Branched-chain {alpha}-Ketoacid Dehydrogenase Complex. J Biol Chem. 2011 Jul 1;286(26):23476-88. Epub 2011 May 3. PMID:21543315 doi:10.1074/jbc.M110.202960
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