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{{STRUCTURE_3rnm|  PDB=3rnm  |  SCENE=  }}
===The crystal structure of the subunit binding of human dihydrolipoamide transacylase (E2b) bound to human dihydrolipoamide dehydrogenase (E3)===
{{ABSTRACT_PUBMED_21543315}}


==Disease==
==The crystal structure of the subunit binding of human dihydrolipoamide transacylase (E2b) bound to human dihydrolipoamide dehydrogenase (E3)==
[[http://www.uniprot.org/uniprot/DLDH_HUMAN 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:[http://omim.org/entry/248600 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. [[http://www.uniprot.org/uniprot/ODB2_HUMAN ODB2_HUMAN]] Defects in DBT are the cause of maple syrup urine disease type 2 (MSUD2) [MIM:[http://omim.org/entry/248600 248600]]. MSUD is an autosomal recessive disorder characterized by mental and physical retardation, feeding problems, and a maple syrup odor to the urine.<ref>PMID:1847055</ref><ref>PMID:9621512</ref>
<StructureSection load='3rnm' size='340' side='right'caption='[[3rnm]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3rnm]] is a 6 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=3RNM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3RNM 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]] 2.4&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3rnm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rnm OCA], [https://pdbe.org/3rnm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3rnm RCSB], [https://www.ebi.ac.uk/pdbsum/3rnm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3rnm ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/DLDH_HUMAN 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:[https://omim.org/entry/248600 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.
== Function ==
[https://www.uniprot.org/uniprot/DLDH_HUMAN 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.
<div style="background-color:#fffaf0;">
== 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.


==Function==
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<ref>PMID:21543315</ref>
[[http://www.uniprot.org/uniprot/DLDH_HUMAN 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. [[http://www.uniprot.org/uniprot/ODB2_HUMAN 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).  


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[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].
</div>
<div class="pdbe-citations 3rnm" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Dihydrolipoamide acetyltransferase|Dihydrolipoamide acetyltransferase]]
*[[Dihydrolipoamide acetyltransferase|Dihydrolipoamide acetyltransferase]]
*[[Dihydrolipoamide acetyltransferase 3D structures|Dihydrolipoamide acetyltransferase 3D structures]]
*[[Dihydrolipoamide dehydrogenase|Dihydrolipoamide dehydrogenase]]
*[[Dihydrolipoamide dehydrogenase|Dihydrolipoamide dehydrogenase]]
 
== References ==
==Reference==
<references/>
<ref group="xtra">PMID:021543315</ref><references group="xtra"/><references/>
__TOC__
[[Category: Dihydrolipoyl dehydrogenase]]
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Brautigam, C A.]]
[[Category: Large Structures]]
[[Category: Chuang, D T.]]
[[Category: Brautigam CA]]
[[Category: Chuang, J C.]]
[[Category: Chuang DT]]
[[Category: Wynn, R M.]]
[[Category: Chuang JC]]
[[Category: Young, B B.]]
[[Category: Wynn RM]]
[[Category: Mitochondrion]]
[[Category: Young BB]]
[[Category: Oxidoreductase-protein binding complex]]
[[Category: Protein-protein interaction]]
[[Category: Redox protein]]
Retrieved from "https://proteopedia.org/3rnm"