5o11

From Proteopedia

(Difference between revisions)

Revision as of 12:15, 26 August 2020

Crystal structure of PIM1 kinase in complex with small-molecule inhibitor

Structural highlights

5o11 is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
NonStd Res:	,
Activity:	Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[PIM1_HUMAN] Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation and thus providing a selective advantage in tumorigenesis. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression and by phosphorylation and inhibition of proapoptotic proteins (BAD, MAP3K5, FOXO3). Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase of transcriptional activity. The stabilization of MYC exerted by PIM1 might explain partly the strong synergism between these two oncogenes in tumorigenesis. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti-apoptotic protein Bcl-X(L)/BCL2L1. Phosphorylation of MAP3K5, an other proapoptotic protein, by PIM1, significantly decreases MAP3K5 kinase activity and inhibits MAP3K5-mediated phosphorylation of JNK and JNK/p38MAPK subsequently reducing caspase-3 activation and cell apoptosis. Stimulates cell cycle progression at the G1-S and G2-M transitions by phosphorylation of CDC25A and CDC25C. Phosphorylation of CDKN1A, a regulator of cell cycle progression at G1, results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. Promote cell cycle progression and tumorigenesis by down-regulating expression of a regulator of cell cycle progression, CDKN1B, at both transcriptional and post-translational levels. Phosphorylation of CDKN1B,induces 14-3-3-proteins binding, nuclear export and proteasome-dependent degradation. May affect the structure or silencing of chromatin by phosphorylating HP1 gamma/CBX3. Acts also as a regulator of homing and migration of bone marrow cells involving functional interaction with the CXCL12-CXCR4 signaling axis.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7]

Publication Abstract from PubMed

PIM1 is an oncogenic kinase overexpressed in a number of cancers where it correlates with poor prognosis. Several studies demonstrated that inhibition of PIM1 activity is an attractive strategy in fighting overexpressing cancers, while distinct structural features of ATP binding pocket make PIM1 an inviting target for the design of selective inhibitors. To facilitate development of specific PIM1 inhibitors, in this study we report three crystal structures of ATP-competitive inhibitors at the ATP binding pocket of PIM1. Two of the reported structures (CX-4945 and Ro-3306) explain the off-target effect on PIM1 of respectively casein kinase 2 and cyclin-dependent kinase 1 dedicated inhibitors. In turn, the structure with CX-6258 demonstrates a binding mode of a potent, selective inhibitor of PIM1, PIM2, PIM3 and Flt-3 kinases. The consequences of our findings for future inhibitor development are discussed.

Structural analysis of PIM1 kinase complexes with ATP-competitive inhibitors.,Bogusz J, Zrubek K, Rembacz KP, Grudnik P, Golik P, Romanowska M, Wladyka B, Dubin G Sci Rep. 2017 Oct 17;7(1):13399. doi: 10.1038/s41598-017-13557-z. PMID:29042609^[8]

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

References

↑ Saris CJ, Domen J, Berns A. The pim-1 oncogene encodes two related protein-serine/threonine kinases by alternative initiation at AUG and CUG. EMBO J. 1991 Mar;10(3):655-64. PMID:1825810
↑ Koike N, Maita H, Taira T, Ariga H, Iguchi-Ariga SM. Identification of heterochromatin protein 1 (HP1) as a phosphorylation target by Pim-1 kinase and the effect of phosphorylation on the transcriptional repression function of HP1(1). FEBS Lett. 2000 Feb 4;467(1):17-21. PMID:10664448
↑ Wang Z, Bhattacharya N, Mixter PF, Wei W, Sedivy J, Magnuson NS. Phosphorylation of the cell cycle inhibitor p21Cip1/WAF1 by Pim-1 kinase. Biochim Biophys Acta. 2002 Dec 16;1593(1):45-55. PMID:12431783
↑ Stout BA, Bates ME, Liu LY, Farrington NN, Bertics PJ. IL-5 and granulocyte-macrophage colony-stimulating factor activate STAT3 and STAT5 and promote Pim-1 and cyclin D3 protein expression in human eosinophils. J Immunol. 2004 Nov 15;173(10):6409-17. PMID:15528381
↑ Bachmann M, Kosan C, Xing PX, Montenarh M, Hoffmann I, Moroy T. The oncogenic serine/threonine kinase Pim-1 directly phosphorylates and activates the G2/M specific phosphatase Cdc25C. Int J Biochem Cell Biol. 2006 Mar;38(3):430-43. Epub 2005 Nov 8. PMID:16356754 doi:10.1016/j.biocel.2005.10.010
↑ Morishita D, Katayama R, Sekimizu K, Tsuruo T, Fujita N. Pim kinases promote cell cycle progression by phosphorylating and down-regulating p27Kip1 at the transcriptional and posttranscriptional levels. Cancer Res. 2008 Jul 1;68(13):5076-85. doi: 10.1158/0008-5472.CAN-08-0634. PMID:18593906 doi:10.1158/0008-5472.CAN-08-0634
↑ Gu JJ, Wang Z, Reeves R, Magnuson NS. PIM1 phosphorylates and negatively regulates ASK1-mediated apoptosis. Oncogene. 2009 Dec 3;28(48):4261-71. doi: 10.1038/onc.2009.276. Epub 2009 Sep 14. PMID:19749799 doi:10.1038/onc.2009.276
↑ Bogusz J, Zrubek K, Rembacz KP, Grudnik P, Golik P, Romanowska M, Wladyka B, Dubin G. Structural analysis of PIM1 kinase complexes with ATP-competitive inhibitors. Sci Rep. 2017 Oct 17;7(1):13399. doi: 10.1038/s41598-017-13557-z. PMID:29042609 doi:http://dx.doi.org/10.1038/s41598-017-13557-z

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5o11"

@@ Line 1: / Line 1: @@
 ==Crystal structure of PIM1 kinase in complex with small-molecule inhibitor==
-<StructureSection load='5o11' size='340' side='right' caption='[[5o11]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
+<StructureSection load='5o11' size='340' side='right'caption='[[5o11]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5o11]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5O11 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5O11 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5o11]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5O11 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5O11 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3NG:5-[(3-CHLOROPHENYL)AMINO]BENZO[C][2,6]NAPHTHYRIDINE-8-CARBOXYLIC+ACID'>3NG</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3NG:5-[(3-CHLOROPHENYL)AMINO]BENZO[C][2,6]NAPHTHYRIDINE-8-CARBOXYLIC+ACID'>3NG</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene></td></tr>
 <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=5o11 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5o11 OCA], [http://pdbe.org/5o11 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5o11 RCSB], [http://www.ebi.ac.uk/pdbsum/5o11 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5o11 ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5o11 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5o11 OCA], [http://pdbe.org/5o11 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5o11 RCSB], [http://www.ebi.ac.uk/pdbsum/5o11 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5o11 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 20: / Line 20: @@
 </div>
 <div class="pdbe-citations 5o11" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Proto-oncogene serine/threonine-protein kinase|Proto-oncogene serine/threonine-protein kinase]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Non-specific serine/threonine protein kinase]]
 [[Category: Bogusz, J]]

5o11

From Proteopedia

Revision as of 12:15, 26 August 2020

Crystal structure of PIM1 kinase in complex with small-molecule inhibitor

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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