5x1w

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m (Protected "5x1w" [edit=sysop:move=sysop])
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'''Unreleased structure'''
 
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The entry 5x1w is ON HOLD until Paper Publication
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==PKM2 in complex with compound 5==
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<StructureSection load='5x1w' size='340' side='right' caption='[[5x1w]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[5x1w]] 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=5X1W OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5X1W FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7Y0:4-[2,3-bis(chloranyl)phenyl]carbonyl-N-[2-[[4-[2,3-bis(chloranyl)phenyl]carbonyl-1-methyl-pyrrol-2-yl]carbonylamino]ethyl]-1-methyl-pyrrole-2-carboxamide'>7Y0</scene>, <scene name='pdbligand=FBP:BETA-FRUCTOSE-1,6-DIPHOSPHATE'>FBP</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5x1v|5x1v]]</td></tr>
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<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>
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<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>
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<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=5x1w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5x1w OCA], [http://pdbe.org/5x1w PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5x1w RCSB], [http://www.ebi.ac.uk/pdbsum/5x1w PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5x1w ProSAT]</span></td></tr>
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</table>
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== Function ==
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[[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Tumor cells switch glucose metabolism to aerobic glycolysis by expressing the pyruvate kinase M2 isoform (PKM2) in a low active form, providing glycolytic intermediates as building blocks for biosynthetic processes, and thereby supporting cell proliferation. Activation of PKM2 should invert aerobic glycolysis to an oxidative metabolism and prevent cancer growth. Thus, PKM2 has gained attention as a promising cancer therapy target. To obtain novel PKM2 activators, we conducted a high-throughput screening (HTS). Among several hit compounds, a fragment-like hit compound with low potency but high ligand efficiency was identified. Two molecules of the hit compound bound at one activator binding site, and the molecules were linked based on the crystal structure. Since this linkage succeeded in maintaining the original position of the hit compound, the obtained compound exhibited highly improved potency in an in vitro assay. The linked compound also showed PKM2 activating activity in a cell based assay, and cellular growth inhibition of the A549 cancer cell line. Discovery of this novel scaffold and binding mode of the linked compound provides a valuable platform for the structure-guided design of PKM2 activators.
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Authors: Matsui, Y., Hanzawa, H.
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Discovery and structure-guided fragment-linking of 4-(2,3-dichlorobenzoyl)-1-methyl-pyrrole-2-carboxamide as a pyruvate kinase M2 activator.,Matsui Y, Yasumatsu I, Asahi T, Kitamura T, Kanai K, Ubukata O, Hayasaka H, Takaishi S, Hanzawa H, Katakura S Bioorg Med Chem. 2017 Jul 1;25(13):3540-3546. doi: 10.1016/j.bmc.2017.05.004., Epub 2017 May 5. PMID:28511909<ref>PMID:28511909</ref>
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Description: PKM2 in complex with compound 4
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Matsui, Y]]
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<div class="pdbe-citations 5x1w" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Pyruvate Kinase|Pyruvate Kinase]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Human]]
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[[Category: Pyruvate kinase]]
[[Category: Hanzawa, H]]
[[Category: Hanzawa, H]]
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[[Category: Matsui, Y]]
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[[Category: Activator]]
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[[Category: Complex]]
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[[Category: Transferase]]

Revision as of 11:58, 16 November 2017

PKM2 in complex with compound 5

5x1w, resolution 3.00Å

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