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| | <StructureSection load='4xyj' size='340' side='right'caption='[[4xyj]], [[Resolution|resolution]] 3.10Å' scene=''> | | <StructureSection load='4xyj' size='340' side='right'caption='[[4xyj]], [[Resolution|resolution]] 3.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4xyj]] is a 8 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=4XYJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XYJ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4xyj]] is a 8 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=4XYJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XYJ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=CO:COBALT+(II)+ION'>CO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=CO:COBALT+(II)+ION'>CO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4xyk|4xyk]]</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=4xyj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xyj OCA], [https://pdbe.org/4xyj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xyj RCSB], [https://www.ebi.ac.uk/pdbsum/4xyj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xyj ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PFKP, PFKF ([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/6-phosphofructokinase 6-phosphofructokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.11 2.7.1.11] </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=4xyj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xyj OCA], [http://pdbe.org/4xyj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4xyj RCSB], [http://www.ebi.ac.uk/pdbsum/4xyj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4xyj ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PFKAP_HUMAN PFKAP_HUMAN]] Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis. | + | [https://www.uniprot.org/uniprot/PFKAP_HUMAN PFKAP_HUMAN] Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis. |
| | <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: 6-phosphofructokinase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Barber, D L]] | + | [[Category: Barber DL]] |
| - | [[Category: Forouhar, F]] | + | [[Category: Forouhar F]] |
| - | [[Category: Structural genomic]]
| + | [[Category: Seetharaman J]] |
| - | [[Category: Seetharaman, J]] | + | [[Category: Szu F-E]] |
| - | [[Category: Szu, F E]] | + | [[Category: Tong L]] |
| - | [[Category: Tong, L]] | + | [[Category: Webb BA]] |
| - | [[Category: Webb, B A]] | + | |
| - | [[Category: Nesg]]
| + | |
| - | [[Category: PSI, Protein structure initiative]]
| + | |
| - | [[Category: Psi-biology]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
PFKAP_HUMAN Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis.
Publication Abstract from PubMed
Phosphofructokinase-1 (PFK1), the 'gatekeeper' of glycolysis, catalyses the committed step of the glycolytic pathway by converting fructose-6-phosphate to fructose-1,6-bisphosphate. Allosteric activation and inhibition of PFK1 by over ten metabolites and in response to hormonal signalling fine-tune glycolytic flux to meet energy requirements. Mutations inhibiting PFK1 activity cause glycogen storage disease type VII, also known as Tarui disease, and mice deficient in muscle PFK1 have decreased fat stores. Additionally, PFK1 is proposed to have important roles in metabolic reprogramming in cancer. Despite its critical role in glucose flux, the biologically relevant crystal structure of the mammalian PFK1 tetramer has not been determined. Here we report the first structures of the mammalian PFK1 tetramer, for the human platelet isoform (PFKP), in complex with ATP-Mg2+ and ADP at 3.1 and 3.4 A, respectively. The structures reveal substantial conformational changes in the enzyme upon nucleotide hydrolysis as well as a unique tetramer interface. Mutations of residues in this interface can affect tetramer formation, enzyme catalysis and regulation, indicating the functional importance of the tetramer. With altered glycolytic flux being a hallmark of cancers, these new structures allow a molecular understanding of the functional consequences of somatic PFK1 mutations identified in human cancers. We characterize three of these mutations and show they have distinct effects on allosteric regulation of PFKP activity and lactate production. The PFKP structural blueprint for somatic mutations as well as the catalytic site can guide therapeutic targeting of PFK1 activity to control dysregulated glycolysis in disease.
Structures of human phosphofructokinase-1 and atomic basis of cancer-associated mutations.,Webb BA, Forouhar F, Szu FE, Seetharaman J, Tong L, Barber DL Nature. 2015 May 18. doi: 10.1038/nature14405. PMID:25985179[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Webb BA, Forouhar F, Szu FE, Seetharaman J, Tong L, Barber DL. Structures of human phosphofructokinase-1 and atomic basis of cancer-associated mutations. Nature. 2015 May 18. doi: 10.1038/nature14405. PMID:25985179 doi:http://dx.doi.org/10.1038/nature14405
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