6p5o: Difference between revisions
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<StructureSection load='6p5o' size='340' side='right'caption='[[6p5o]], [[Resolution|resolution]] 1.49Å' scene=''> | <StructureSection load='6p5o' size='340' side='right'caption='[[6p5o]], [[Resolution|resolution]] 1.49Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6p5o]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[6p5o]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6P5O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6P5O FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.49Å</td></tr> | ||
<tr id=' | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=O2Y:3-[(carboxymethyl)sulfanyl]pyridine-2-carboxylic+acid'>O2Y</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=6p5o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p5o OCA], [https://pdbe.org/6p5o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6p5o RCSB], [https://www.ebi.ac.uk/pdbsum/6p5o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6p5o ProSAT]</span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/PCKGC_RAT PCKGC_RAT] Catalyzes the conversion of oxaloacetate (OAA) to phosphoenolpyruvate (PEP), the rate-limiting step in the metabolic pathway that produces glucose from lactate and other precursors derived from the citric acid cycle. | ||
<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: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Rattus norvegicus]] | ||
[[Category: | [[Category: Holyoak T]] | ||
[[Category: | [[Category: Mcleod MJ]] | ||
Latest revision as of 10:23, 11 October 2023
The structure of rat cytosolic PEPCK in complex with 3-(carboxymethylthiol)-picolinic acidThe structure of rat cytosolic PEPCK in complex with 3-(carboxymethylthiol)-picolinic acid
Structural highlights
FunctionPCKGC_RAT Catalyzes the conversion of oxaloacetate (OAA) to phosphoenolpyruvate (PEP), the rate-limiting step in the metabolic pathway that produces glucose from lactate and other precursors derived from the citric acid cycle. Publication Abstract from PubMedPhosphoenolpyruvate carboxykinase (PEPCK) has traditionally been characterized for its role in the first committed step of gluconeogenesis. The current understanding of PEPCK's metabolic role has recently expanded to include it serving as a general mediator of tricarboxylic acid cycle flux. Selective inhibition of PEPCK in vivo and in vitro has been achieved with 3-mercaptopicolinic acid (MPA) (Ki approximately 8 muM), whose mechanism of inhibition has been elucidated only recently. On the basis of crystallographic and mechanistic data of various inhibitors of PEPCK, MPA was used as the initial chemical scaffold to create a potentially more selective inhibitor, 3-[(carboxymethyl)thio]picolinic acid (CMP), which has been characterized both structurally and kinetically here. These data demonstrate that CMP acts as a competitive inhibitor at the OAA/PEP binding site, with its picolinic acid moiety coordinating directly with the M1 metal in the active site (Ki approximately 29-55 muM). The extended carboxy tail occupies a secondary binding cleft that was previously shown could be occupied by sulfoacetate (Ki approximately 82 muM) and for the first time demonstrates the simultaneous occupation of both OAA/PEP subsites by a single molecular structure. By occupying both the OAA/PEP binding subsites simultaneously, CMP and similar molecules can potentially be used as a starting point for the creation of additional selective inhibitors of PEPCK. Characterization of 3-[(Carboxymethyl)thio]picolinic Acid: A Novel Inhibitor of Phosphoenolpyruvate Carboxykinase.,Mcleod MJ, Krismanich AP, Assoud A, Dmitrienko GI, Holyoak T Biochemistry. 2019 Sep 17;58(37):3918-3926. doi: 10.1021/acs.biochem.9b00583., Epub 2019 Sep 6. PMID:31461616[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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