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==Crystal structure of human GDP-D-mannose 4,6-dehydratase (E157Q) in complex with GDP-Man== | ==Crystal structure of human GDP-D-mannose 4,6-dehydratase (E157Q) in complex with GDP-Man== | ||
<StructureSection load='6gpk' size='340' side='right' caption='[[6gpk]], [[Resolution|resolution]] 1.47Å' scene=''> | <StructureSection load='6gpk' size='340' side='right'caption='[[6gpk]], [[Resolution|resolution]] 1.47Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6gpk]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GPK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GPK FirstGlance]. <br> | <table><tr><td colspan='2'>[[6gpk]] 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=6GPK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GPK FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GDD:GUANOSINE-5-DIPHOSPHATE-ALPHA-D-MANNOSE'>GDD</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GDD:GUANOSINE-5-DIPHOSPHATE-ALPHA-D-MANNOSE'>GDD</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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='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='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=6gpk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gpk OCA], [http://pdbe.org/6gpk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6gpk RCSB], [http://www.ebi.ac.uk/pdbsum/6gpk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6gpk 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=6gpk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gpk OCA], [http://pdbe.org/6gpk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6gpk RCSB], [http://www.ebi.ac.uk/pdbsum/6gpk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6gpk ProSAT]</span></td></tr> | ||
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== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/GMDS_HUMAN GMDS_HUMAN]] Conversion of GDP-D-mannose to GDP-4-keto-6-D-deoxymannose. | [[http://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;"> | |||
== Publication Abstract from PubMed == | |||
Biosynthesis of 6-deoxy sugars, including l-fucose, involves a mechanistically complex, enzymatic 4,6-dehydration of hexose nucleotide precursors as the first committed step. Here, we determined pre- and postcatalytic complex structures of the human GDP-mannose 4,6-dehydratase at atomic resolution. These structures together with results of molecular dynamics simulation and biochemical characterization of wildtype and mutant enzymes reveal elusive mechanistic details of water elimination from GDP-mannose C5'' and C6'', coupled to NADP-mediated hydride transfer from C4'' to C6''. We show that concerted acid-base catalysis from only two active-site groups, Tyr179 and Glu157, promotes a syn 1,4-elimination from an enol (not an enolate) intermediate. We also show that the overall multistep catalytic reaction involves the fewest position changes of enzyme and substrate groups and that it proceeds under conserved exploitation of the basic (minimal) catalytic machinery of short-chain dehydrogenase/reductases. | |||
A Parsimonious Mechanism of Sugar Dehydration by Human GDP-Mannose-4,6-dehydratase.,Pfeiffer M, Johansson C, Krojer T, Kavanagh KL, Oppermann U, Nidetzky B ACS Catal. 2019 Apr 5;9(4):2962-2968. doi: 10.1021/acscatal.9b00064. Epub 2019, Mar 1. PMID:30984471<ref>PMID:30984471</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6gpk" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: GDP-mannose 4,6-dehydratase]] | [[Category: GDP-mannose 4,6-dehydratase]] | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Arrowsmith, C H]] | [[Category: Arrowsmith, C H]] | ||
[[Category: Bountra, C]] | [[Category: Bountra, C]] | ||
Latest revision as of 10:55, 24 April 2019
Crystal structure of human GDP-D-mannose 4,6-dehydratase (E157Q) in complex with GDP-ManCrystal structure of human GDP-D-mannose 4,6-dehydratase (E157Q) in complex with GDP-Man
Structural highlights
Function[GMDS_HUMAN] Conversion of GDP-D-mannose to GDP-4-keto-6-D-deoxymannose. Publication Abstract from PubMedBiosynthesis of 6-deoxy sugars, including l-fucose, involves a mechanistically complex, enzymatic 4,6-dehydration of hexose nucleotide precursors as the first committed step. Here, we determined pre- and postcatalytic complex structures of the human GDP-mannose 4,6-dehydratase at atomic resolution. These structures together with results of molecular dynamics simulation and biochemical characterization of wildtype and mutant enzymes reveal elusive mechanistic details of water elimination from GDP-mannose C5 and C6, coupled to NADP-mediated hydride transfer from C4 to C6. We show that concerted acid-base catalysis from only two active-site groups, Tyr179 and Glu157, promotes a syn 1,4-elimination from an enol (not an enolate) intermediate. We also show that the overall multistep catalytic reaction involves the fewest position changes of enzyme and substrate groups and that it proceeds under conserved exploitation of the basic (minimal) catalytic machinery of short-chain dehydrogenase/reductases. A Parsimonious Mechanism of Sugar Dehydration by Human GDP-Mannose-4,6-dehydratase.,Pfeiffer M, Johansson C, Krojer T, Kavanagh KL, Oppermann U, Nidetzky B ACS Catal. 2019 Apr 5;9(4):2962-2968. doi: 10.1021/acscatal.9b00064. Epub 2019, Mar 1. PMID:30984471[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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