3gg8: Difference between revisions
New page: '''Unreleased structure''' The entry 3gg8 is ON HOLD Authors: Wernimont, A.K., Lew, J., Allali-Hassani, A., Vedadi, M., Bochkarev, A., Arrowsmith, C.H., Bountra, C., Weigelt, J., Edward... |
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The | ==Crystal structure of the Toxoplasma gondii Pyruvate Kinase N terminal truncated== | ||
<StructureSection load='3gg8' size='340' side='right'caption='[[3gg8]], [[Resolution|resolution]] 2.21Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3gg8]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Toxoplasma_gondii Toxoplasma gondii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3GG8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3GG8 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]] 2.21Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</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=3gg8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3gg8 OCA], [https://pdbe.org/3gg8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3gg8 RCSB], [https://www.ebi.ac.uk/pdbsum/3gg8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3gg8 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q969A2_TOXGO Q969A2_TOXGO] | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/gg/3gg8_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3gg8 ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
BACKGROUND: Pyruvate kinase (PK), which catalyzes the final step in glycolysis converting phosphoenolpyruvate to pyruvate, is a central metabolic regulator in most organisms. Consequently PK represents an attractive therapeutic target in cancer and human pathogens, like Apicomplexans. The phylum Aplicomplexa, a group of exclusively parasitic organisms, includes the genera Plasmodium, Cryptosporidium and Toxoplasma, the etiological agents of malaria, cryptosporidiosis and toxoplasmosis respectively. Toxoplasma gondii infection causes a mild illness and is a very common infection affecting nearly one third of the world's population. METHODOLOGY/PRINCIPAL FINDINGS: We have determined the crystal structure of the PK1 enzyme from T. gondii, with the B domain in the open and closed conformations. We have also characterized its enzymatic activity and confirmed glucose-6-phosphate as its allosteric activator. This is the first description of a PK enzyme in a closed inactive conformation without any bound substrate. Comparison of the two tetrameric TgPK1 structures indicates a reorientation of the monomers with a concomitant change in the buried surface among adjacent monomers. The change in the buried surface was associated with significant B domain movements in one of the interacting monomers. CONCLUSIONS: We hypothesize that a loop in the interface between the A and B domains plays an important role linking the position of the B domain to the buried surface among monomers through two alpha-helices. The proposed model links the catalytic cycle of the enzyme with its domain movements and highlights the contribution of the interface between adjacent subunits. In addition, an unusual ordered conformation was observed in one of the allosteric binding domains and it is related to a specific apicomplexan insertion. The sequence and structural particularity would explain the atypical activation by a mono-phosphorylated sugar. The sum of peculiarities raises this enzyme as an emerging target for drug discovery. | |||
The crystal structure of Toxoplasma gondii pyruvate kinase 1.,Bakszt R, Wernimont A, Allali-Hassani A, Mok MW, Hills T, Hui R, Pizarro JC PLoS One. 2010 Sep 14;5(9):e12736. PMID:20856875<ref>PMID:20856875</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3gg8" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Pyruvate kinase 3D structures|Pyruvate kinase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Toxoplasma gondii]] | |||
[[Category: Allali-Hassani A]] | |||
[[Category: Arrowsmith CH]] | |||
[[Category: Bochkarev A]] | |||
[[Category: Bountra C]] | |||
[[Category: Edwards AM]] | |||
[[Category: Hills T]] | |||
[[Category: Hui R]] | |||
[[Category: Lew J]] | |||
[[Category: Pizarro JC]] | |||
[[Category: Schapira M]] | |||
[[Category: Vedadi M]] | |||
[[Category: Weigelt J]] | |||
[[Category: Wernimont AK]] | |||
Latest revision as of 10:05, 6 September 2023
Crystal structure of the Toxoplasma gondii Pyruvate Kinase N terminal truncatedCrystal structure of the Toxoplasma gondii Pyruvate Kinase N terminal truncated
Structural highlights
FunctionEvolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedBACKGROUND: Pyruvate kinase (PK), which catalyzes the final step in glycolysis converting phosphoenolpyruvate to pyruvate, is a central metabolic regulator in most organisms. Consequently PK represents an attractive therapeutic target in cancer and human pathogens, like Apicomplexans. The phylum Aplicomplexa, a group of exclusively parasitic organisms, includes the genera Plasmodium, Cryptosporidium and Toxoplasma, the etiological agents of malaria, cryptosporidiosis and toxoplasmosis respectively. Toxoplasma gondii infection causes a mild illness and is a very common infection affecting nearly one third of the world's population. METHODOLOGY/PRINCIPAL FINDINGS: We have determined the crystal structure of the PK1 enzyme from T. gondii, with the B domain in the open and closed conformations. We have also characterized its enzymatic activity and confirmed glucose-6-phosphate as its allosteric activator. This is the first description of a PK enzyme in a closed inactive conformation without any bound substrate. Comparison of the two tetrameric TgPK1 structures indicates a reorientation of the monomers with a concomitant change in the buried surface among adjacent monomers. The change in the buried surface was associated with significant B domain movements in one of the interacting monomers. CONCLUSIONS: We hypothesize that a loop in the interface between the A and B domains plays an important role linking the position of the B domain to the buried surface among monomers through two alpha-helices. The proposed model links the catalytic cycle of the enzyme with its domain movements and highlights the contribution of the interface between adjacent subunits. In addition, an unusual ordered conformation was observed in one of the allosteric binding domains and it is related to a specific apicomplexan insertion. The sequence and structural particularity would explain the atypical activation by a mono-phosphorylated sugar. The sum of peculiarities raises this enzyme as an emerging target for drug discovery. The crystal structure of Toxoplasma gondii pyruvate kinase 1.,Bakszt R, Wernimont A, Allali-Hassani A, Mok MW, Hills T, Hui R, Pizarro JC PLoS One. 2010 Sep 14;5(9):e12736. PMID:20856875[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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