View source for 3eo3

==Crystal structure of the N-acetylmannosamine kinase domain of human GNE protein==
<StructureSection load='3eo3' size='340' side='right' caption='[[3eo3]], [[Resolution|resolution]] 2.84&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3eo3]] is a 3 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=3EO3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3EO3 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GNE, GLCNE ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=3eo3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3eo3 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3eo3 RCSB], [http://www.ebi.ac.uk/pdbsum/3eo3 PDBsum]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/GLCNE_HUMAN GLCNE_HUMAN]] Defects in GNE are a cause of sialuria (SIALURIA) [MIM:[http://omim.org/entry/269921 269921]]; also known as sialuria French type. In sialuria, free sialic acid accumulates in the cytoplasm and gram quantities of neuraminic acid are secreted in the urine. The metabolic defect involves lack of feedback inhibition of UDP-GlcNAc 2-epimerase by CMP-Neu5Ac, resulting in constitutive overproduction of free Neu5Ac. Clinical features include variable degrees of developmental delay, coarse facial features and hepatomegaly. Sialuria inheritance is autosomal dominant.<ref>PMID:2808337</ref> <ref>PMID:10330343</ref> <ref>PMID:10356312</ref> <ref>PMID:11326336</ref>   Defects in GNE are the cause of inclusion body myopathy type 2 (IBM2) [MIM:[http://omim.org/entry/600737 600737]]. Hereditary inclusion body myopathies are a group of neuromuscular disorders characterized by adult onset, slowly progressive distal and proximal weakness and a typical muscle pathology including rimmed vacuoles and filamentous inclusions. IBM2 is an autosomal recessive disorder affecting mainly leg muscles, but with an unusual distribution that spares the quadriceps as also observed in Nonaka myopathy.<ref>PMID:11528398</ref> <ref>PMID:12409274</ref> <ref>PMID:12473769</ref> <ref>PMID:12473780</ref> <ref>PMID:12497639</ref> <ref>PMID:12811782</ref> <ref>PMID:15146476</ref>   Defects in GNE are the cause of Nonaka myopathy (NM) [MIM:[http://omim.org/entry/605820 605820]]; also known as distal myopathy with rimmed vacuoles (DMRV). NM is an autosomal recessive muscular disorder, allelic to inclusion body myopathy 2. It is characterized by weakness of the anterior compartment of the lower limbs with onset in early adulthood, and sparing of the quadriceps muscles. As the inclusion body myopathy, NM is histologically characterized by the presence of numerous rimmed vacuoles without inflammatory changes in muscle specimens.<ref>PMID:12325084</ref> <ref>PMID:11916006</ref> <ref>PMID:12177386</ref> <ref>PMID:12473753</ref> <ref>PMID:12913203</ref>  
== Function ==
[[http://www.uniprot.org/uniprot/GLCNE_HUMAN GLCNE_HUMAN]] Regulates and initiates biosynthesis of N-acetylneuraminic acid (NeuAc), a precursor of sialic acids. Plays an essential role in early development (By similarity). Required for normal sialylation in hematopoietic cells. Sialylation is implicated in cell adhesion, signal transduction, tumorigenicity and metastatic behavior of malignant cells.<ref>PMID:10334995</ref>  
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/eo/3eo3_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
BACKGROUND: UDP-GlcNAc 2-epimerase/ManNAc 6-kinase, GNE, is a bi-functional enzyme that plays a key role in sialic acid biosynthesis. Mutations of the GNE protein cause sialurea or autosomal recessive inclusion body myopathy/Nonaka myopathy. GNE is the only human protein that contains a kinase domain belonging to the ROK (repressor, ORF, kinase) family. PRINCIPAL FINDINGS: We solved the structure of the GNE kinase domain in the ligand-free state. The protein exists predominantly as a dimer in solution, with small populations of monomer and higher-order oligomer in equilibrium with the dimer. Crystal packing analysis reveals the existence of a crystallographic hexamer, and that the kinase domain dimerizes through the C-lobe subdomain. Mapping of disease-related missense mutations onto the kinase domain structure revealed that the mutation sites could be classified into four different groups based on the location - dimer interface, interlobar helices, protein surface, or within other secondary structural elements. CONCLUSIONS: The crystal structure of the kinase domain of GNE provides a structural basis for understanding disease-causing mutations and a model of hexameric wild type full length enzyme. ENHANCED VERSION: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1.

Crystal structure of the N-acetylmannosamine kinase domain of GNE.,Tong Y, Tempel W, Nedyalkova L, Mackenzie F, Park HW PLoS One. 2009 Oct 20;4(10):e7165. PMID:19841673<ref>PMID:19841673</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Arrowsmith, C H]]
[[Category: Bochkarev, A]]
[[Category: Bountra, C]]
[[Category: Edwards, A M]]
[[Category: Hong, B]]
[[Category: MacKenzie, F]]
[[Category: Nedyalkova, L]]
[[Category: Park, H]]
[[Category: Rabeh, W M]]
[[Category: Structural genomic]]
[[Category: Tempel, W]]
[[Category: Tong, Y]]
[[Category: Weigelt, J]]
[[Category: Allosteric enzyme]]
[[Category: Atp-binding]]
[[Category: Disease mutation]]
[[Category: Isomerase]]
[[Category: Kinase]]
[[Category: Multifunctional enzyme]]
[[Category: Non-protein kinase]]
[[Category: Nucleotide-binding]]
[[Category: Phosphoprotein]]
[[Category: Sgc]]
[[Category: Sialic acid biosynthesis]]
[[Category: Transferase]]