7uc2
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[7uc2]] 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=7UC2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UC2 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7uc2]] 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=7UC2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UC2 FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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">Electron Microscopy, [[Resolution|Resolution]] 2.5Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</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=7uc2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7uc2 OCA], [https://pdbe.org/7uc2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7uc2 RCSB], [https://www.ebi.ac.uk/pdbsum/7uc2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7uc2 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=7uc2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7uc2 OCA], [https://pdbe.org/7uc2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7uc2 RCSB], [https://www.ebi.ac.uk/pdbsum/7uc2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7uc2 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
| - | + | [https://www.uniprot.org/uniprot/G6PD_HUMAN G6PD_HUMAN] Defects in G6PD are the cause of chronic non-spherocytic hemolytic anemia (CNSHA) [MIM:[https://omim.org/entry/305900 305900]. Deficiency of G6PD is associated with hemolytic anemia in two different situations. First, in areas in which malaria has been endemic, G6PD-deficiency alleles have reached high frequencies (1% to 50%) and deficient individuals, though essentially asymptomatic in the steady state, have a high risk of acute hemolytic attacks. Secondly, sporadic cases of G6PD deficiency occur at a very low frequencies, and they usually present a more severe phenotype. Several types of CNSHA are recognized. Class-I variants are associated with severe NSHA; class-II have an activity <10% of normal; class-III have an activity of 10% to 60% of normal; class-IV have near normal activity.<ref>PMID:1611091</ref> | |
== Function == | == Function == | ||
| - | + | [https://www.uniprot.org/uniprot/G6PD_HUMAN G6PD_HUMAN] Produces pentose sugars for nucleic acid synthesis and main producer of NADPH reducing power. | |
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
Human glucose-6-phosphate dehydrogenase (G6PD) is the main cellular source of NADPH, and thus plays a key role in maintaining reduced glutathione to protect cells from oxidative stress disorders such as hemolytic anemia. G6PD is a multimeric enzyme that uses the cofactors beta-D-glucose 6-phosphate (G6P) and "catalytic" NADP(+) (NADP(+)c), as well as a "structural" NADP(+) (NADP(+)s) located approximately 25 A from the active site, to generate NADPH. While X-ray crystallographic and biochemical studies have revealed a role for NADP(+)s in maintaining the catalytic activity by stabilizing the multimeric G6PD conformation, other potential roles for NADP(+)s have not been evaluated. Here, we determined the high resolution cryo-electron microscopy structures of human wild-type G6PD in the absence of bound ligands and a catalytic G6PD-D200N mutant bound to NADP(+)c and NADP(+)s in the absence or presence of G6P. A comparison of these structures, together with previously reported structures, reveals that the unliganded human G6PD forms a mixture of dimers and tetramers with similar overall folds, and binding of NADP(+)s induces a structural ordering of a C-terminal extension region and allosterically regulates G6P binding and catalysis. These studies have implications for understanding G6PD deficiencies and for therapy of G6PD-mediated disorders. | Human glucose-6-phosphate dehydrogenase (G6PD) is the main cellular source of NADPH, and thus plays a key role in maintaining reduced glutathione to protect cells from oxidative stress disorders such as hemolytic anemia. G6PD is a multimeric enzyme that uses the cofactors beta-D-glucose 6-phosphate (G6P) and "catalytic" NADP(+) (NADP(+)c), as well as a "structural" NADP(+) (NADP(+)s) located approximately 25 A from the active site, to generate NADPH. While X-ray crystallographic and biochemical studies have revealed a role for NADP(+)s in maintaining the catalytic activity by stabilizing the multimeric G6PD conformation, other potential roles for NADP(+)s have not been evaluated. Here, we determined the high resolution cryo-electron microscopy structures of human wild-type G6PD in the absence of bound ligands and a catalytic G6PD-D200N mutant bound to NADP(+)c and NADP(+)s in the absence or presence of G6P. A comparison of these structures, together with previously reported structures, reveals that the unliganded human G6PD forms a mixture of dimers and tetramers with similar overall folds, and binding of NADP(+)s induces a structural ordering of a C-terminal extension region and allosterically regulates G6P binding and catalysis. These studies have implications for understanding G6PD deficiencies and for therapy of G6PD-mediated disorders. | ||
| - | Allosteric role of a structural NADP(+) molecule in glucose-6-phosphate dehydrogenase activity.,Wei X, Kixmoeller K, Baltrusaitis E, Yang X, Marmorstein R Proc Natl Acad Sci U S A. 2022 Jul 19;119(29):e2119695119. doi:, 10.1073/pnas.2119695119. Epub 2022 Jul 12. PMID:35858355<ref>PMID:35858355</ref> | + | Allosteric role of a structural NADP(+) molecule in glucose-6-phosphate dehydrogenase activity.,Wei X, Kixmoeller K, Baltrusaitis E, Yang X, Marmorstein R Proc Natl Acad Sci U S A. 2022 Jul 19;119(29):e2119695119. doi: , 10.1073/pnas.2119695119. Epub 2022 Jul 12. PMID:35858355<ref>PMID:35858355</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
Current revision
Structure of G6PD-D200N tetramer bound to NADP+ with no symmetry applied
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