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| ==Structure of the GH99 endo-alpha-mannosidase from Bacteroides xylanisolvens in complex with glucose-1,3-isofagomine== | | ==Structure of the GH99 endo-alpha-mannosidase from Bacteroides xylanisolvens in complex with glucose-1,3-isofagomine== |
| <StructureSection load='4ad2' size='340' side='right' caption='[[4ad2]], [[Resolution|resolution]] 2.10Å' scene=''> | | <StructureSection load='4ad2' size='340' side='right'caption='[[4ad2]], [[Resolution|resolution]] 2.10Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[4ad2]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Bacteroides_sp._xb1a Bacteroides sp. xb1a]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4AD2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4AD2 FirstGlance]. <br> | | <table><tr><td colspan='2'>[[4ad2]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Bacteroides_xylanisolvens_XB1A Bacteroides xylanisolvens XB1A]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4AD2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4AD2 FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=IFM:5-HYDROXYMETHYL-3,4-DIHYDROXYPIPERIDINE'>IFM</scene></td></tr> | | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1Å</td></tr> |
| <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ad0|4ad0]], [[4ad4|4ad4]], [[4acy|4acy]], [[4ad3|4ad3]], [[4ad1|4ad1]], [[4ad5|4ad5]], [[4acz|4acz]]</td></tr> | | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=IFM:5-HYDROXYMETHYL-3,4-DIHYDROXYPIPERIDINE'>IFM</scene></td></tr> |
| <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glycoprotein_endo-alpha-1,2-mannosidase Glycoprotein endo-alpha-1,2-mannosidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.130 3.2.1.130] </span></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=4ad2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ad2 OCA], [https://pdbe.org/4ad2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ad2 RCSB], [https://www.ebi.ac.uk/pdbsum/4ad2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ad2 ProSAT]</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=4ad2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ad2 OCA], [http://pdbe.org/4ad2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ad2 RCSB], [http://www.ebi.ac.uk/pdbsum/4ad2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ad2 ProSAT]</span></td></tr> | |
| </table> | | </table> |
| <div style="background-color:#fffaf0;">
| | == Function == |
| == Publication Abstract from PubMed == | | [https://www.uniprot.org/uniprot/D6D1V7_9BACE D6D1V7_9BACE] |
| N-linked glycans play key roles in protein folding, stability, and function. Biosynthetic modification of N-linked glycans, within the endoplasmic reticulum, features sequential trimming and readornment steps. One unusual enzyme, endo-alpha-mannosidase, cleaves mannoside linkages internally within an N-linked glycan chain, short circuiting the classical N-glycan biosynthetic pathway. Here, using two bacterial orthologs, we present the first structural and mechanistic dissection of endo-alpha-mannosidase. Structures solved at resolutions 1.7-2.1 A reveal a (beta/alpha)(8) barrel fold in which the catalytic center is present in a long substrate-binding groove, consistent with cleavage within the N-glycan chain. Enzymatic cleavage of authentic Glc(1/3)Man(9)GlcNAc(2) yields Glc(1/3)-Man. Using the bespoke substrate alpha-Glc-1,3-alpha-Man fluoride, the enzyme was shown to act with retention of anomeric configuration. Complexes with the established endo-alpha-mannosidase inhibitor alpha-Glc-1,3-deoxymannonojirimycin and a newly developed inhibitor, alpha-Glc-1,3-isofagomine, and with the reducing-end product alpha-1,2-mannobiose structurally define the -2 to +2 subsites of the enzyme. These structural and mechanistic data provide a foundation upon which to develop new enzyme inhibitors targeting the hijacking of N-glycan synthesis in viral disease and cancer.
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| Structural and mechanistic insight into N-glycan processing by endo-alpha-mannosidase.,Thompson AJ, Williams RJ, Hakki Z, Alonzi DS, Wennekes T, Gloster TM, Songsrirote K, Thomas-Oates JE, Wrodnigg TM, Spreitz J, Stutz AE, Butters TD, Williams SJ, Davies GJ Proc Natl Acad Sci U S A. 2012 Jan 4. PMID:22219371<ref>PMID:22219371</ref>
| | ==See Also== |
| | | *[[Mannosidase 3D structures|Mannosidase 3D structures]] |
| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| <div class="pdbe-citations 4ad2" style="background-color:#fffaf0;"></div>
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| == References == | |
| <references/>
| |
| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Bacteroides sp. xb1a]] | | [[Category: Bacteroides xylanisolvens XB1A]] |
| [[Category: Glycoprotein endo-alpha-1,2-mannosidase]] | | [[Category: Large Structures]] |
| [[Category: Alonzi, D S]] | | [[Category: Alonzi DS]] |
| [[Category: Butters, T D]] | | [[Category: Butters TD]] |
| [[Category: Davies, G J]] | | [[Category: Davies GJ]] |
| [[Category: Gloster, T M]] | | [[Category: Gloster TM]] |
| [[Category: Hakki, Z]] | | [[Category: Hakki Z]] |
| [[Category: Songsrirote, K]] | | [[Category: Songsrirote K]] |
| [[Category: Spreitz, J]] | | [[Category: Spreitz J]] |
| [[Category: Stuetz, A E]] | | [[Category: Stuetz AE]] |
| [[Category: Thomas-Oates, J E]] | | [[Category: Thomas-Oates JE]] |
| [[Category: Thompson, A J]] | | [[Category: Thompson AJ]] |
| [[Category: Wennekes, T]] | | [[Category: Wennekes T]] |
| [[Category: Williams, R J]] | | [[Category: Williams RJ]] |
| [[Category: Williams, S J]] | | [[Category: Williams SJ]] |
| [[Category: Wrodnigg, T M]] | | [[Category: Wrodnigg TM]] |
| [[Category: Cazy]]
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| [[Category: Endomannosidase]]
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| [[Category: Enzyme-carbohydrate interaction]]
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| [[Category: Glycoside hydrolase gh99]]
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| [[Category: Hydrolase]]
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| [[Category: Mannose glycosidase inhibition]]
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