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| | <StructureSection load='6pyp' size='340' side='right'caption='[[6pyp]], [[Resolution|resolution]] 1.95Å' scene=''> | | <StructureSection load='6pyp' size='340' side='right'caption='[[6pyp]], [[Resolution|resolution]] 1.95Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6pyp]] 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=6PYP OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6PYP FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6pyp]] 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=6PYP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PYP FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3SY:2,2-BIS(HYDROXYMETHYL)PROPANE-1,3-DIOL'>3SY</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=POP:PYROPHOSPHATE+2-'>POP</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]] 1.95Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GPD1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3SY:2,2-BIS(HYDROXYMETHYL)PROPANE-1,3-DIOL'>3SY</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=POP:PYROPHOSPHATE+2-'>POP</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glycerol-3-phosphate_dehydrogenase_(NAD(+)) Glycerol-3-phosphate dehydrogenase (NAD(+))], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.8 1.1.1.8] </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=6pyp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pyp OCA], [https://pdbe.org/6pyp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6pyp RCSB], [https://www.ebi.ac.uk/pdbsum/6pyp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6pyp ProSAT]</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=6pyp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pyp OCA], [http://pdbe.org/6pyp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pyp RCSB], [http://www.ebi.ac.uk/pdbsum/6pyp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pyp ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/GPDA_HUMAN GPDA_HUMAN]] Defects in GPD1 are a cause of hypertriglyceridemia, transient infantile (HTGTI) [MIM:[http://omim.org/entry/614480 614480]]. An autosomal recessive disorder characterized by onset of moderate to severe transient hypertriglyceridemia in infancy that normalizes with age. The hypertriglyceridemia is associated with hepatomegaly, moderately elevated transaminases, persistent fatty liver, and the development of hepatic fibrosis.<ref>PMID:22226083</ref> | + | [https://www.uniprot.org/uniprot/GPDA_HUMAN GPDA_HUMAN] Defects in GPD1 are a cause of hypertriglyceridemia, transient infantile (HTGTI) [MIM:[https://omim.org/entry/614480 614480]. An autosomal recessive disorder characterized by onset of moderate to severe transient hypertriglyceridemia in infancy that normalizes with age. The hypertriglyceridemia is associated with hepatomegaly, moderately elevated transaminases, persistent fatty liver, and the development of hepatic fibrosis.<ref>PMID:22226083</ref> |
| - | <div style="background-color:#fffaf0;">
| + | == Function == |
| - | == Publication Abstract from PubMed == | + | [https://www.uniprot.org/uniprot/GPDA_HUMAN GPDA_HUMAN] |
| - | Glycerol-3-phosphate dehydrogenase is a biomedically important enzyme that plays a crucial role in lipid biosynthesis. It is activated by a ligand-gated conformational change that is necessary for the enzyme to reach a catalytically competent conformation capable of efficient transition-state stabilization. While the human form (hlGPDH) has been the subject of extensive structural and biochemical studies, corresponding computational studies to support and extend experimental observations have been lacking. We perform here detailed empirical valence bond and Hamiltonian replica exchange molecular dynamics simulations of wild-type hlGPDH and its variants, as well as providing a crystal structure of the binary hlGPDH.NAD R269A variant where the enzyme is present in the open conformation. We estimated the activation free energies for the hydride transfer reaction in wild-type and substituted hlGPDH and investigated the effect of mutations on catalysis from a detailed structural study. In particular, the K120A and R269A variants increase both the volume and solvent exposure of the active site, with concomitant loss of catalytic activity. In addition, the R269 side chain interacts with both the Q295 side chain on the catalytic loop, and the substrate phosphodianion. Our structural data and simulations illustrate the critical role of this side chain in facilitating the closure of hlGPDH into a catalytically competent conformation, through modulating the flexibility of a key catalytic loop (292-LNGQKL-297). This, in turn, rationalizes a tremendous 41,000 fold decrease experimentally in the turnover number, k cat, upon truncating this residue, as loop closure is essential for both correct positioning of key catalytic residues in the active site, as well as sequestering the active site from the solvent. Taken together, our data highlight the importance of this ligand-gated conformational change in catalysis, a feature that can be exploited both for protein engineering and for the design of allosteric inhibitors targeting this biomedically important enzyme.
| + | |
| | | | |
| - | Modeling the Role of a Flexible Loop and Active Site Side Chains in Hydride Transfer Catalyzed by Glycerol-3-phosphate Dehydrogenase.,Mhashal AR, Romero-Rivera A, Mydy LS, Cristobal JR, Gulick AM, Richard JP, Kamerlin SCL ACS Catal. 2020 Oct 2;10(19):11253-11267. doi: 10.1021/acscatal.0c02757. Epub, 2020 Sep 3. PMID:33042609<ref>PMID:33042609</ref>
| + | ==See Also== |
| - | | + | *[[Glycerol-3-phosphate dehydrogenase 3D structures|Glycerol-3-phosphate dehydrogenase 3D structures]] |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 6pyp" style="background-color:#fffaf0;"></div>
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Gulick, A M]] | + | [[Category: Gulick AM]] |
| - | [[Category: Dehydrogenase]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
6pyp is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.95Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
GPDA_HUMAN Defects in GPD1 are a cause of hypertriglyceridemia, transient infantile (HTGTI) [MIM:614480. An autosomal recessive disorder characterized by onset of moderate to severe transient hypertriglyceridemia in infancy that normalizes with age. The hypertriglyceridemia is associated with hepatomegaly, moderately elevated transaminases, persistent fatty liver, and the development of hepatic fibrosis.[1]
Function
GPDA_HUMAN
See Also
References
- ↑ Basel-Vanagaite L, Zevit N, Har Zahav A, Guo L, Parathath S, Pasmanik-Chor M, McIntyre AD, Wang J, Albin-Kaplanski A, Hartman C, Marom D, Zeharia A, Badir A, Shoerman O, Simon AJ, Rechavi G, Shohat M, Hegele RA, Fisher EA, Shamir R. Transient infantile hypertriglyceridemia, fatty liver, and hepatic fibrosis caused by mutated GPD1, encoding glycerol-3-phosphate dehydrogenase 1. Am J Hum Genet. 2012 Jan 13;90(1):49-60. doi: 10.1016/j.ajhg.2011.11.028. Epub, 2012 Jan 5. PMID:22226083 doi:10.1016/j.ajhg.2011.11.028
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