9fcw
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of human Glucose-6-phosphate isomerase with maleate ligand== | |
| + | <StructureSection load='9fcw' size='340' side='right'caption='[[9fcw]], [[Resolution|resolution]] 1.40Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9fcw]] 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=9FCW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9FCW FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.4Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MAE:MALEIC+ACID'>MAE</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</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=9fcw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9fcw OCA], [https://pdbe.org/9fcw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9fcw RCSB], [https://www.ebi.ac.uk/pdbsum/9fcw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9fcw ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [https://www.uniprot.org/uniprot/G6PI_HUMAN G6PI_HUMAN] Defects in GPI are the cause of hemolytic anemia non-spherocytic due to glucose phosphate isomerase deficiency (HA-GPID) [MIM:[https://omim.org/entry/613470 613470]. It is a form of anemia in which there is no abnormal hemoglobin or spherocytosis. It is caused by glucose phosphate isomerase deficiency. Severe GPI deficiency can be associated with hydrops fetalis, immediate neonatal death and neurological impairment. | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/G6PI_HUMAN G6PI_HUMAN] Besides it's role as a glycolytic enzyme, mammalian GPI can function as a tumor-secreted cytokine and an angiogenic factor (AMF) that stimulates endothelial cell motility. GPI is also a neurotrophic factor (Neuroleukin) for spinal and sensory neurons.<ref>PMID:11004567</ref> <ref>PMID:11437381</ref> <ref>PMID:12163179</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Modulation of enzyme activity by metabolites represents the most efficient and rapid way of controlling metabolism. Investigating enzyme-metabolite interactions can deepen our understanding of metabolic control and aid in identifying enzyme modulators with potential therapeutic applications. These interactions vary in strength, with dissociation constants (K(d)) ranging from strong (nm) to weak (mum-mm). However, weak interactions are often overlooked due to the challenges in studying them. Despite this, weak modulators can reveal unknown binding modes and serve as starting points for compound optimization. In this study, we aimed to identify metabolites that weakly modulate the activity of human glucose-6-phosphate isomerase (GPI) and triosephosphate isomerase (TPI), which are potential therapeutic targets in tumor glycolysis. Through a combination of activity and binding assays, the screening revealed multiple weak inhibitors for the two targets, causing partial attenuation of their activity, with K(d) and K(i) in the low mm range. X-ray crystallography revealed six orthosteric ligands binding to the active sites - four inhibitors of GPI and two of TPI. Our findings underscore the role of weak interactions in enzyme regulation and may provide structural insights that could aid the design of inhibitors targeting human GPI and TPI in cancer intervention. | ||
| - | + | Human glycolysis isomerases are inhibited by weak metabolite modulators.,Jonatansdottir YY, Rolfsson O, Hjorleifsson JG FEBS J. 2025 Feb 27. doi: 10.1111/febs.70049. PMID:40014465<ref>PMID:40014465</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 9fcw" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Hjorleifsson GJ]] | ||
| + | [[Category: Jonatansdottir YY]] | ||
Current revision
Crystal structure of human Glucose-6-phosphate isomerase with maleate ligand
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