3me3: Difference between revisions
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==Activator-Bound Structure of Human Pyruvate Kinase M2== | |||
<StructureSection load='3me3' size='340' side='right' caption='[[3me3]], [[Resolution|resolution]] 1.95Å' scene=''> | |||
{ | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3me3]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ME3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ME3 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3SZ:3-{[4-(2,3-DIHYDRO-1,4-BENZODIOXIN-6-YLSULFONYL)-1,4-DIAZEPAN-1-YL]SULFONYL}ANILINE'>3SZ</scene>, <scene name='pdbligand=FBP:BETA-FRUCTOSE-1,6-DIPHOSPHATE'>FBP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PKM2, OIP3, PK2, PK3, PKM ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3me3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3me3 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3me3 RCSB], [http://www.ebi.ac.uk/pdbsum/3me3 PDBsum]</span></td></tr> | |||
</table> | |||
== 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/me/3me3_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/chain_selection.php?pdb_ID=2ata ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism. | |||
Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis.,Anastasiou D, Yu Y, Israelsen WJ, Jiang JK, Boxer MB, Hong BS, Tempel W, Dimov S, Shen M, Jha A, Yang H, Mattaini KR, Metallo CM, Fiske BP, Courtney KD, Malstrom S, Khan TM, Kung C, Skoumbourdis AP, Veith H, Southall N, Walsh MJ, Brimacombe KR, Leister W, Lunt SY, Johnson ZR, Yen KE, Kunii K, Davidson SM, Christofk HR, Austin CP, Inglese J, Harris MH, Asara JM, Stephanopoulos G, Salituro FG, Jin S, Dang L, Auld DS, Park HW, Cantley LC, Thomas CJ, Heiden MG Nat Chem Biol. 2012 Aug 26. doi: 10.1038/nchembio.1060. PMID:22922757<ref>PMID:22922757</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Pyruvate Kinase|Pyruvate Kinase]] | *[[Pyruvate Kinase|Pyruvate Kinase]] | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Pyruvate kinase]] | [[Category: Pyruvate kinase]] | ||
[[Category: Arrowsmith, C H | [[Category: Arrowsmith, C H]] | ||
[[Category: Auld, D | [[Category: Auld, D]] | ||
[[Category: Bochkarev, A | [[Category: Bochkarev, A]] | ||
[[Category: Bountra, C | [[Category: Bountra, C]] | ||
[[Category: Boxer, M | [[Category: Boxer, M]] | ||
[[Category: Dimov, S | [[Category: Dimov, S]] | ||
[[Category: Edwards, A M | [[Category: Edwards, A M]] | ||
[[Category: Hong, B | [[Category: Hong, B]] | ||
[[Category: Inglese, J | [[Category: Inglese, J]] | ||
[[Category: Jianq, J K | [[Category: Jianq, J K]] | ||
[[Category: Min, S | [[Category: Min, S]] | ||
[[Category: Park, H | [[Category: Park, H]] | ||
[[Category: | [[Category: Structural genomic]] | ||
[[Category: Skoumbourdis, A | [[Category: Skoumbourdis, A]] | ||
[[Category: Southall, N | [[Category: Southall, N]] | ||
[[Category: Tempel, W | [[Category: Tempel, W]] | ||
[[Category: Thomas, C | [[Category: Thomas, C]] | ||
[[Category: Weigelt, J | [[Category: Weigelt, J]] | ||
[[Category: Activator]] | [[Category: Activator]] | ||
[[Category: Sgc]] | [[Category: Sgc]] | ||
[[Category: Transferase]] | [[Category: Transferase]] | ||
Revision as of 11:35, 18 December 2014
Activator-Bound Structure of Human Pyruvate Kinase M2Activator-Bound Structure of Human Pyruvate Kinase M2
Structural highlights
Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedCancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis.,Anastasiou D, Yu Y, Israelsen WJ, Jiang JK, Boxer MB, Hong BS, Tempel W, Dimov S, Shen M, Jha A, Yang H, Mattaini KR, Metallo CM, Fiske BP, Courtney KD, Malstrom S, Khan TM, Kung C, Skoumbourdis AP, Veith H, Southall N, Walsh MJ, Brimacombe KR, Leister W, Lunt SY, Johnson ZR, Yen KE, Kunii K, Davidson SM, Christofk HR, Austin CP, Inglese J, Harris MH, Asara JM, Stephanopoulos G, Salituro FG, Jin S, Dang L, Auld DS, Park HW, Cantley LC, Thomas CJ, Heiden MG Nat Chem Biol. 2012 Aug 26. doi: 10.1038/nchembio.1060. PMID:22922757[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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