4rpp: Difference between revisions

Revision as of 05:08, 25 August 2022

crystal structure of PKM2-K422R mutant bound with FBP

Structural highlights

4rpp is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	FBP
Related:	4qgc, 4qg9, 4qg8, 4qg6
Activity:	Pyruvate kinase, with EC number 2.7.1.40
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[KPYM_HUMAN] Glycolytic enzyme that catalyzes the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP. Stimulates POU5F1-mediated transcriptional activation. Plays a general role in caspase independent cell death of tumor cells. The ratio betwween the highly active tetrameric form and nearly inactive dimeric form determines whether glucose carbons are channeled to biosynthetic processes or used for glycolytic ATP production. The transition between the 2 forms contributes to the control of glycolysis and is important for tumor cell proliferation and survival.^[1] ^[2] ^[3]

Publication Abstract from PubMed

Pyruvate kinase isoform M2 (PKM2) converts phosphoenolpyruvate (PEP) to pyruvate and plays an important role in cancer metabolism. Here, we show that post-translational modifications and a patient-derived mutation regulate pyruvate kinase activity of PKM2 through modulating the conformation of the PKM2 tetramer. We determined crystal structures of human PKM2 mutants and proposed a "seesaw" model to illustrate conformational changes between an inactive T-state and an active R-state tetramers of PKM2. Biochemical and structural analyses demonstrate that PKM2Y105E (phosphorylation mimic of Y105) decreases pyruvate kinase activity by inhibiting FBP (fructose 1,6-bisphosphate)-induced R-state formation, and PKM2K305Q (acetylation mimic of K305) abolishes the activity by hindering tetramer formation. K422R, a patient-derived mutation of PKM2, favors a stable, inactive T-state tetramer because of strong intermolecular interactions. Our study reveals the mechanism for dynamic regulation of PKM2 by post-translational modifications and a patient-derived mutation and provides a structural basis for further investigation of other modifications and mutations of PKM2 yet to be discovered.

Structural insight into mechanisms for dynamic regulation of PKM2.,Wang P, Sun C, Zhu T, Xu Y Protein Cell. 2015 Feb 4. PMID:25645022^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Stetak A, Veress R, Ovadi J, Csermely P, Keri G, Ullrich A. Nuclear translocation of the tumor marker pyruvate kinase M2 induces programmed cell death. Cancer Res. 2007 Feb 15;67(4):1602-8. PMID:17308100 doi:10.1158/0008-5472.CAN-06-2870
↑ Lee J, Kim HK, Han YM, Kim J. Pyruvate kinase isozyme type M2 (PKM2) interacts and cooperates with Oct-4 in regulating transcription. Int J Biochem Cell Biol. 2008;40(5):1043-54. doi: 10.1016/j.biocel.2007.11.009., Epub 2007 Nov 29. PMID:18191611 doi:10.1016/j.biocel.2007.11.009
↑ Luo W, Hu H, Chang R, Zhong J, Knabel M, O'Meally R, Cole RN, Pandey A, Semenza GL. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell. 2011 May 27;145(5):732-44. doi: 10.1016/j.cell.2011.03.054. PMID:21620138 doi:10.1016/j.cell.2011.03.054
↑ Wang P, Sun C, Zhu T, Xu Y. Structural insight into mechanisms for dynamic regulation of PKM2. Protein Cell. 2015 Feb 4. PMID:25645022 doi:https://dx.doi.org/10.1007/s13238-015-0132-x

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Stetak A, Veress R, Ovadi J, Csermely P, Keri G, Ullrich A. Nuclear translocation of the tumor marker pyruvate kinase M2 induces programmed cell death. Cancer Res. 2007 Feb 15;67(4):1602-8. PMID:17308100 doi:10.1158/0008-5472.CAN-06-2870

[2] Lee J, Kim HK, Han YM, Kim J. Pyruvate kinase isozyme type M2 (PKM2) interacts and cooperates with Oct-4 in regulating transcription. Int J Biochem Cell Biol. 2008;40(5):1043-54. doi: 10.1016/j.biocel.2007.11.009., Epub 2007 Nov 29. PMID:18191611 doi:10.1016/j.biocel.2007.11.009

[3] Luo W, Hu H, Chang R, Zhong J, Knabel M, O'Meally R, Cole RN, Pandey A, Semenza GL. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell. 2011 May 27;145(5):732-44. doi: 10.1016/j.cell.2011.03.054. PMID:21620138 doi:10.1016/j.cell.2011.03.054

[4] Wang P, Sun C, Zhu T, Xu Y. Structural insight into mechanisms for dynamic regulation of PKM2. Protein Cell. 2015 Feb 4. PMID:25645022 doi:https://dx.doi.org/10.1007/s13238-015-0132-x

[1]

[2]

[3]

[4]

@@ Line 3: / Line 3: @@
 <StructureSection load='4rpp' size='340' side='right'caption='[[4rpp]], [[Resolution|resolution]] 2.58&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4rpp]] is a 4 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=4RPP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RPP FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4rpp]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RPP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RPP FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FBP:BETA-FRUCTOSE-1,6-DIPHOSPHATE'>FBP</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FBP:BETA-FRUCTOSE-1,6-DIPHOSPHATE'>FBP</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4qgc|4qgc]], [[4qg9|4qg9]], [[4qg8|4qg8]], [[4qg6|4qg6]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[4qgc|4qgc]], [[4qg9|4qg9]], [[4qg8|4qg8]], [[4qg6|4qg6]]</div></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PKM, OIP3, PK2, PK3, PKM2 ([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'>[https://en.wikipedia.org/wiki/Pyruvate_kinase Pyruvate kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.40 2.7.1.40] </span></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Pyruvate_kinase Pyruvate kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.40 2.7.1.40] </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=4rpp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rpp OCA], [https://pdbe.org/4rpp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4rpp RCSB], [https://www.ebi.ac.uk/pdbsum/4rpp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4rpp ProSAT]</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=4rpp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rpp OCA], [http://pdbe.org/4rpp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rpp RCSB], [http://www.ebi.ac.uk/pdbsum/4rpp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4rpp ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/KPYM_HUMAN KPYM_HUMAN]] Glycolytic enzyme that catalyzes the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP. Stimulates POU5F1-mediated transcriptional activation. Plays a general role in caspase independent cell death of tumor cells. The ratio betwween the highly active tetrameric form and nearly inactive dimeric form determines whether glucose carbons are channeled to biosynthetic processes or used for glycolytic ATP production. The transition between the 2 forms contributes to the control of glycolysis and is important for tumor cell proliferation and survival.<ref>PMID:17308100</ref> <ref>PMID:18191611</ref> <ref>PMID:21620138</ref>
+[[https://www.uniprot.org/uniprot/KPYM_HUMAN KPYM_HUMAN]] Glycolytic enzyme that catalyzes the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP. Stimulates POU5F1-mediated transcriptional activation. Plays a general role in caspase independent cell death of tumor cells. The ratio betwween the highly active tetrameric form and nearly inactive dimeric form determines whether glucose carbons are channeled to biosynthetic processes or used for glycolytic ATP production. The transition between the 2 forms contributes to the control of glycolysis and is important for tumor cell proliferation and survival.<ref>PMID:17308100</ref> <ref>PMID:18191611</ref> <ref>PMID:21620138</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 22: @@
 ==See Also==
-*[[Pyruvate Kinase|Pyruvate Kinase]]
+*[[Pyruvate kinase 3D structures|Pyruvate kinase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Pyruvate kinase]]

4rpp: Difference between revisions

Revision as of 05:08, 25 August 2022

crystal structure of PKM2-K422R mutant bound with FBP

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools