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| | <StructureSection load='6uo6' size='340' side='right'caption='[[6uo6]], [[Resolution|resolution]] 2.15Å' scene=''> | | <StructureSection load='6uo6' size='340' side='right'caption='[[6uo6]], [[Resolution|resolution]] 2.15Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6uo6]] is a 2 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=6UO6 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6UO6 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6uo6]] is a 2 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=6UO6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6UO6 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.15Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5epc|5epc]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PGM1 ([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=6uo6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uo6 OCA], [https://pdbe.org/6uo6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6uo6 RCSB], [https://www.ebi.ac.uk/pdbsum/6uo6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6uo6 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/Phosphoglucomutase Phosphoglucomutase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.4.2.2 5.4.2.2] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6uo6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uo6 OCA], [http://pdbe.org/6uo6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6uo6 RCSB], [http://www.ebi.ac.uk/pdbsum/6uo6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6uo6 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/PGM1_HUMAN PGM1_HUMAN]] PGM-CDG;Glycogen storage disease due to phosphoglucomutase deficiency. The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/PGM1_HUMAN PGM1_HUMAN] PGM-CDG;Glycogen storage disease due to phosphoglucomutase deficiency. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PGM1_HUMAN PGM1_HUMAN]] This enzyme participates in both the breakdown and synthesis of glucose. | + | [https://www.uniprot.org/uniprot/PGM1_HUMAN PGM1_HUMAN] This enzyme participates in both the breakdown and synthesis of glucose. |
| | <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: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Phosphoglucomutase]]
| + | [[Category: Beamer LJ]] |
| - | [[Category: Beamer, L J]] | + | [[Category: Stiers KM]] |
| - | [[Category: Stiers, K M]] | + | |
| - | [[Category: Enzyme]]
| + | |
| - | [[Category: Isomerase]]
| + | |
| - | [[Category: Missense variant]]
| + | |
| Structural highlights
Disease
PGM1_HUMAN PGM-CDG;Glycogen storage disease due to phosphoglucomutase deficiency. The disease is caused by mutations affecting the gene represented in this entry.
Function
PGM1_HUMAN This enzyme participates in both the breakdown and synthesis of glucose.
Publication Abstract from PubMed
Missense variants of human phosphoglucomutase 1 (PGM1) cause the inherited metabolic disease known as PGM1 deficiency. This condition is categorised as both a glycogen storage disease and a congenital disorder of glycosylation. Approximately 20 missense variants of PGM1 are linked to PGM1 deficiency, and biochemical studies have suggested that they fall into two general categories: those affecting the active site and catalytic efficiency, and those that appear to impair protein folding and/or stability. In this study, we characterise a novel variant of Arg422, a residue distal from the active site of PGM1 and the site of a previously identified disease-related variant (Arg422Trp). In prior studies, the R422W variant was found to produce insoluble protein in a recombinant expression system, precluding further in vitro characterisation. Here we investigate an alternative variant of this residue, Arg422Gln, which is amenable to experimental characterisation presumably due to its more conservative physicochemical substitution. Biochemical, crystallographic, and computational studies of R422Q establish that this variant causes only minor changes in catalytic efficiency and 3D structure, but is nonetheless dramatically reduced in stability. Unexpectedly, binding of a substrate analog is found to further destabilise the protein, in contrast to its stabilising effect on wild-type PGM1 and several other missense variants. This work establishes Arg422 as a lynchpin residue for the stability of PGM1 and supports the impairment of protein stability as a pathomechanism for variants that cause PGM1 deficiency. SYNOPSIS: Biochemical and structural studies of a missense variant far from the active site of human PGM1 identify a residue with a key role in enzyme stability.
A missense variant remote from the active site impairs stability of human phosphoglucomutase 1.,Stiers KM, Hansen RP, Daghlas BA, Mason KN, Zhu JS, Jakeman DL, Beamer LJ J Inherit Metab Dis. 2020 Feb 14. doi: 10.1002/jimd.12222. PMID:32057119[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Stiers KM, Hansen RP, Daghlas BA, Mason KN, Zhu JS, Jakeman DL, Beamer LJ. A missense variant remote from the active site impairs stability of human phosphoglucomutase 1. J Inherit Metab Dis. 2020 Feb 14. doi: 10.1002/jimd.12222. PMID:32057119 doi:http://dx.doi.org/10.1002/jimd.12222
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