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| | <StructureSection load='2gcg' size='340' side='right'caption='[[2gcg]], [[Resolution|resolution]] 2.20Å' scene=''> | | <StructureSection load='2gcg' size='340' side='right'caption='[[2gcg]], [[Resolution|resolution]] 2.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2gcg]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GCG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2GCG FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2gcg]] 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=2GCG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2GCG FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DGY:(2R)-2,3-DIHYDROXYPROPANOIC+ACID'>DGY</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</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]] 2.2Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Glyoxylate_reductase_(NADP(+)) Glyoxylate reductase (NADP(+))], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.79 1.1.1.79] </span></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DGY:(2R)-2,3-DIHYDROXYPROPANOIC+ACID'>DGY</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=2gcg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2gcg OCA], [https://pdbe.org/2gcg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2gcg RCSB], [https://www.ebi.ac.uk/pdbsum/2gcg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2gcg ProSAT]</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=2gcg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2gcg OCA], [https://pdbe.org/2gcg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2gcg RCSB], [https://www.ebi.ac.uk/pdbsum/2gcg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2gcg ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[https://www.uniprot.org/uniprot/GRHPR_HUMAN GRHPR_HUMAN]] Defects in GRHPR are the cause of hyperoxaluria primary type 2 (HP2) [MIM:[https://omim.org/entry/260000 260000]]; also known as primary hyperoxaluria type II (PH2). HP2 is a disorder where the main clinical manifestation is calcium oxalate nephrolithiasis though chronic as well as terminal renal insufficiency has been described. It is characterized by an elevated urinary excretion of oxalate and L-glycerate.<ref>PMID:10484776</ref>
| + | [https://www.uniprot.org/uniprot/GRHPR_HUMAN GRHPR_HUMAN] Defects in GRHPR are the cause of hyperoxaluria primary type 2 (HP2) [MIM:[https://omim.org/entry/260000 260000]; also known as primary hyperoxaluria type II (PH2). HP2 is a disorder where the main clinical manifestation is calcium oxalate nephrolithiasis though chronic as well as terminal renal insufficiency has been described. It is characterized by an elevated urinary excretion of oxalate and L-glycerate.<ref>PMID:10484776</ref> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/GRHPR_HUMAN GRHPR_HUMAN]] Enzyme with hydroxy-pyruvate reductase, glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities. Reduces hydroxypyruvate to D-glycerate, glyoxylate to glycolate oxidizes D-glycerate to hydroxypyruvate.
| + | [https://www.uniprot.org/uniprot/GRHPR_HUMAN GRHPR_HUMAN] Enzyme with hydroxy-pyruvate reductase, glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities. Reduces hydroxypyruvate to D-glycerate, glyoxylate to glycolate oxidizes D-glycerate to hydroxypyruvate. |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Booth, M P.S]] | + | [[Category: Booth MPS]] |
| - | [[Category: Brady, R L]] | + | [[Category: Brady RL]] |
| - | [[Category: Conners, R]] | + | [[Category: Conners R]] |
| - | [[Category: Rumsby, G]] | + | [[Category: Rumsby G]] |
| - | [[Category: Formate/glycerate dehydrogenase substrate-binding domain]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
Disease
GRHPR_HUMAN Defects in GRHPR are the cause of hyperoxaluria primary type 2 (HP2) [MIM:260000; also known as primary hyperoxaluria type II (PH2). HP2 is a disorder where the main clinical manifestation is calcium oxalate nephrolithiasis though chronic as well as terminal renal insufficiency has been described. It is characterized by an elevated urinary excretion of oxalate and L-glycerate.[1]
Function
GRHPR_HUMAN Enzyme with hydroxy-pyruvate reductase, glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities. Reduces hydroxypyruvate to D-glycerate, glyoxylate to glycolate oxidizes D-glycerate to hydroxypyruvate.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Human glyoxylate reductase/hydroxypyruvate reductase (GRHPR) is a D-2-hydroxy-acid dehydrogenase that plays a critical role in the removal of the metabolic by-product glyoxylate from within the liver. Deficiency of this enzyme is the underlying cause of primary hyperoxaluria type 2 (PH2) and leads to increased urinary oxalate levels, formation of kidney stones and renal failure. Here we describe the crystal structure of human GRHPR at 2.2 A resolution. There are four copies of GRHPR in the crystallographic asymmetric unit: in each homodimer, one subunit forms a ternary (enzyme+NADPH+reduced substrate) complex, and the other a binary (enzyme+NADPH) form. The spatial arrangement of the two enzyme domains is the same in binary and ternary forms. This first crystal structure of a true ternary complex of an enzyme from this family demonstrates the relationship of substrate and catalytic residues within the active site, confirming earlier proposals of the mode of substrate binding, stereospecificity and likely catalytic mechanism for these enzymes. GRHPR has an unusual substrate specificity, preferring glyoxylate and hydroxypyruvate, but not pyruvate. A tryptophan residue (Trp141) from the neighbouring subunit of the dimer is projected into the active site region and appears to contribute to the selectivity for hydroxypyruvate. This first crystal structure of a human GRHPR enzyme also explains the deleterious effects of naturally occurring missense mutations of this enzyme that lead to PH2.
Structural basis of substrate specificity in human glyoxylate reductase/hydroxypyruvate reductase.,Booth MP, Conners R, Rumsby G, Brady RL J Mol Biol. 2006 Jun 30;360(1):178-89. Epub 2006 May 22. PMID:16756993[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Cramer SD, Ferree PM, Lin K, Milliner DS, Holmes RP. The gene encoding hydroxypyruvate reductase (GRHPR) is mutated in patients with primary hyperoxaluria type II. Hum Mol Genet. 1999 Oct;8(11):2063-9. PMID:10484776
- ↑ Booth MP, Conners R, Rumsby G, Brady RL. Structural basis of substrate specificity in human glyoxylate reductase/hydroxypyruvate reductase. J Mol Biol. 2006 Jun 30;360(1):178-89. Epub 2006 May 22. PMID:16756993 doi:10.1016/j.jmb.2006.05.018
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