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| | ==Crystal Structure of GDP-mannose 4,6 dehydratase bound to a GDP-fucose based inhibitor== | | ==Crystal Structure of GDP-mannose 4,6 dehydratase bound to a GDP-fucose based inhibitor== |
| - | <StructureSection load='5in4' size='340' side='right' caption='[[5in4]], [[Resolution|resolution]] 1.60Å' scene=''> | + | <StructureSection load='5in4' size='340' side='right'caption='[[5in4]], [[Resolution|resolution]] 1.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5in4]] is a 4 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=5IN4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5IN4 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5in4]] is a 4 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=5IN4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5IN4 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6CK:[(2R,3S,4R,5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]methyl+(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(trifluoromethyl)tetrahydro-2H-pyran-2-yl+dihydrogen+diphosphate+(non-preferred+name)'>6CK</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</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]] 1.6Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5in5|5in5]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6CK:[(2R,3S,4R,5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]methyl+(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(trifluoromethyl)tetrahydro-2H-pyran-2-yl+dihydrogen+diphosphate+(non-preferred+name)'>6CK</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GMDS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5in4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5in4 OCA], [https://pdbe.org/5in4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5in4 RCSB], [https://www.ebi.ac.uk/pdbsum/5in4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5in4 ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/GDP-mannose_4,6-dehydratase GDP-mannose 4,6-dehydratase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.2.1.47 4.2.1.47] </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=5in4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5in4 OCA], [http://pdbe.org/5in4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5in4 RCSB], [http://www.ebi.ac.uk/pdbsum/5in4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5in4 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GMDS_HUMAN GMDS_HUMAN]] Conversion of GDP-D-mannose to GDP-4-keto-6-D-deoxymannose. | + | [https://www.uniprot.org/uniprot/GMDS_HUMAN GMDS_HUMAN] Conversion of GDP-D-mannose to GDP-4-keto-6-D-deoxymannose. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: GDP-mannose 4,6-dehydratase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Sickmier, E A]] | + | [[Category: Sickmier EA]] |
| - | [[Category: Dehydratase]]
| + | |
| - | [[Category: Antibody fucosylation]]
| + | |
| - | [[Category: Gdp-mannose 4]]
| + | |
| - | [[Category: Lyase-inhibitor complex]]
| + | |
| Structural highlights
Function
GMDS_HUMAN Conversion of GDP-D-mannose to GDP-4-keto-6-D-deoxymannose.
Publication Abstract from PubMed
The efficacy of therapeutic antibodies that induce antibody-dependent cellular cytotoxicity can be improved by reduced fucosylation. Consequently, fucosylation is a critical product attribute of monoclonal antibodies produced as protein therapeutics. Small molecule fucosylation inhibitors have also shown promise as potential therapeutics in animal models of tumors, arthritis, and sickle cell disease. Potent small molecule metabolic inhibitors of cellular protein fucosylation, 6,6,6-trifluorofucose per-O-acetate and 6,6,6-trifluorofucose (fucostatin I), were identified that reduces the fucosylation of recombinantly expressed antibodies in cell culture in a concentration-dependent fashion enabling the controlled modulation of protein fucosylation levels. 6,6,6-Trifluorofucose binds at an allosteric site of GDP-mannose 4,6-dehydratase (GMD) as revealed for the first time by the X-ray cocrystal structure of a bound allosteric GMD inhibitor. 6,6,6-Trifluorofucose was found to be incorporated in place of fucose at low levels (<1%) in the glycans of recombinantly expressed antibodies. A fucose-1-phosphonate analog, fucostatin II, was designed that inhibits fucosylation with no incorporation into antibody glycans, allowing the production of afucosylated antibodies in which the incorporation of non-native sugar is completely absent-a key advantage in the production of therapeutic antibodies, especially biosimilar antibodies. Inhibitor structure-activity relationships, identification of cellular and inhibitor metabolites in inhibitor-treated cells, fucose competition studies, and the production of recombinant antibodies with varying levels of fucosylation are described.
Facile Modulation of Antibody Fucosylation with Small Molecule Fucostatin Inhibitors and Cocrystal Structure with GDP-Mannose 4,6-Dehydratase.,Allen JG, Mujacic M, Frohn MJ, Pickrell AJ, Kodama P, Bagal D, San Miguel T, Sickmier EA, Osgood S, Swietlow A, Li V, Jordan JB, Kim KW, Rousseau AC, Kim YJ, Caille S, Achmatowicz M, Thiel O, Fotsch CH, Reddy P, McCarter JD ACS Chem Biol. 2016 Aug 11. PMID:27434622[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Allen JG, Mujacic M, Frohn MJ, Pickrell AJ, Kodama P, Bagal D, San Miguel T, Sickmier EA, Osgood S, Swietlow A, Li V, Jordan JB, Kim KW, Rousseau AC, Kim YJ, Caille S, Achmatowicz M, Thiel O, Fotsch CH, Reddy P, McCarter JD. Facile Modulation of Antibody Fucosylation with Small Molecule Fucostatin Inhibitors and Cocrystal Structure with GDP-Mannose 4,6-Dehydratase. ACS Chem Biol. 2016 Aug 11. PMID:27434622 doi:http://dx.doi.org/10.1021/acschembio.6b00460
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