View source for 3som


==crystal structure of human MMACHC==
<StructureSection load='3som' size='340' side='right'caption='[[3som]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3som]] is a 16 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=3SOM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SOM 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=5AD:5-DEOXYADENOSINE'>5AD</scene>, <scene name='pdbligand=DHL:2-AMINO-ETHANETHIOL'>DHL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FLC:CITRATE+ANION'>FLC</scene>, <scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</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=3som FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3som OCA], [https://pdbe.org/3som PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3som RCSB], [https://www.ebi.ac.uk/pdbsum/3som PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3som ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/MMAC_HUMAN MMAC_HUMAN] Methylmalonic acidemia with homocystinuria, type cblC. The disease is caused by mutations affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/MMAC_HUMAN MMAC_HUMAN] May be involved in the binding and intracellular trafficking of cobalamin (vitamin B12).
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Defects in the MMACHC gene represent the most common disorder of cobalamin (Cbl) metabolism, affecting synthesis of the enzyme cofactors adenosyl-Cbl and methyl-Cbl. The encoded MMACHC protein binds intracellular Cbl derivatives with different upper axial ligands and exhibits flavin mononucleotide (FMN)-dependent decyanase activity toward cyano-Cbl as well as glutathione (GSH)-dependent dealkylase activity toward alkyl-Cbls. We determined the structure of human MMACHC.adenosyl-Cbl complex, revealing a tailor-made nitroreductase scaffold which binds adenosyl-Cbl in a "base-off, five-coordinate" configuration for catalysis. We further identified an arginine-rich pocket close to the Cbl binding site responsible for GSH binding and dealkylation activity. Mutation of these highly conserved arginines, including a replication of the prevalent MMACHC missense mutation, Arg161Gln, disrupts GSH binding and dealkylation. We further showed that two Cbl-binding monomers dimerize to mediate the reciprocal exchange of a conserved "PNRRP" loop from both subunits, serving as a protein cap for the upper axial ligand in trans and required for proper dealkylation activity. Our dimeric structure is supported by solution studies, where dimerization is triggered upon binding its substrate adenosyl-Cbl or cofactor FMN. Together our data provide a structural framework to understanding catalytic function and disease mechanism for this multifunctional enzyme.

Structure of MMACHC reveals an arginine-rich pocket and a domain-swapped dimer for its B12 processing function.,Froese DS, Krojer T, Wu X, Shrestha R, Kiyani W, von Delft F, Gravel RA, Oppermann U, Yue WW Biochemistry. 2012 Jun 26;51(25):5083-90. Epub 2012 Jun 14. PMID:22642810<ref>PMID:22642810</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3som" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Arrowsmith CH]]
[[Category: Bountra C]]
[[Category: Edwards A]]
[[Category: Froese DS]]
[[Category: Gileadi C]]
[[Category: Gravel RA]]
[[Category: Krojer T]]
[[Category: Muniz JR]]
[[Category: Oppermann U]]
[[Category: Vollmar M]]
[[Category: Weigelt J]]
[[Category: Yue WW]]
[[Category: Von Delft F]]