6tti: Difference between revisions

Latest revision as of 13:19, 22 May 2024

PKM2 in complex with Compound 6PKM2 in complex with Compound 6

6tti, resolution 2.50Å

Structural highlights

6tti is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.5Å
Ligands:
Experimental data:	Check
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

Recent advances in cryo-electron microscopy (EM) structure determination have pushed the resolutions obtainable by the method into the range widely considered to be of utility for drug discovery. Here, we review the use of cryo-EM in fragment-based drug discovery (FBDD) based on in-house method development. We demonstrate not only that cryo-EM can reveal details of the molecular interactions between fragments and a protein, but also that the current reproducibility, quality, and throughput are compatible with FBDD. We exemplify this using the test system beta-galactosidase (Bgal) and the oncology target pyruvate kinase 2 (PKM2).

Fragment-based drug discovery using cryo-EM.,Saur M, Hartshorn MJ, Dong J, Reeks J, Bunkoczi G, Jhoti H, Williams PA Drug Discov Today. 2019 Dec 23. pii: S1359-6446(19)30465-9. doi:, 10.1016/j.drudis.2019.12.006. PMID:31877353^[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
↑ Saur M, Hartshorn MJ, Dong J, Reeks J, Bunkoczi G, Jhoti H, Williams PA. Fragment-based drug discovery using cryo-EM. Drug Discov Today. 2019 Dec 23. pii: S1359-6446(19)30465-9. doi:, 10.1016/j.drudis.2019.12.006. PMID:31877353 doi:http://dx.doi.org/10.1016/j.drudis.2019.12.006

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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] Saur M, Hartshorn MJ, Dong J, Reeks J, Bunkoczi G, Jhoti H, Williams PA. Fragment-based drug discovery using cryo-EM. Drug Discov Today. 2019 Dec 23. pii: S1359-6446(19)30465-9. doi:, 10.1016/j.drudis.2019.12.006. PMID:31877353 doi:http://dx.doi.org/10.1016/j.drudis.2019.12.006

[1]

[2]

[3]

[4]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6tti is ON HOLD
+==PKM2 in complex with Compound 6==
+<SX load='6tti' size='340' side='right' viewer='molstar' caption='[[6tti]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6tti]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TTI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TTI FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=FBP:BETA-FRUCTOSE-1,6-DIPHOSPHATE'>FBP</scene>, <scene name='pdbligand=NXE:~{N}-[3-(trifluoromethyl)-1,2-oxazol-5-yl]ethanamide'>NXE</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=6tti FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tti OCA], [https://pdbe.org/6tti PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tti RCSB], [https://www.ebi.ac.uk/pdbsum/6tti PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tti ProSAT]</span></td></tr>
+</table>
+== Function ==
+[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 ==
+Recent advances in cryo-electron microscopy (EM) structure determination have pushed the resolutions obtainable by the method into the range widely considered to be of utility for drug discovery. Here, we review the use of cryo-EM in fragment-based drug discovery (FBDD) based on in-house method development. We demonstrate not only that cryo-EM can reveal details of the molecular interactions between fragments and a protein, but also that the current reproducibility, quality, and throughput are compatible with FBDD. We exemplify this using the test system beta-galactosidase (Bgal) and the oncology target pyruvate kinase 2 (PKM2).
-Authors:
+Fragment-based drug discovery using cryo-EM.,Saur M, Hartshorn MJ, Dong J, Reeks J, Bunkoczi G, Jhoti H, Williams PA Drug Discov Today. 2019 Dec 23. pii: S1359-6446(19)30465-9. doi:, 10.1016/j.drudis.2019.12.006. PMID:31877353<ref>PMID:31877353</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 6tti" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Pyruvate kinase 3D structures|Pyruvate kinase 3D structures]]
+== References ==
+<references/>
+__TOC__
+</SX>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Bunkoczi G]]
+[[Category: Dong J]]
+[[Category: Hartshorn MJ]]
+[[Category: Jhoti H]]
+[[Category: Reeks J]]
+[[Category: Saur M]]
+[[Category: Williams PA]]

6tti: Difference between revisions

Latest revision as of 13:19, 22 May 2024

PKM2 in complex with Compound 6PKM2 in complex with Compound 6

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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6tti: Difference between revisions

Latest revision as of 13:19, 22 May 2024

PKM2 in complex with Compound 6PKM2 in complex with Compound 6

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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