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4x7q

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Revision as of 00:20, 26 January 2017

PIM2 kinase in complex with Compound 1s

Structural highlights

4x7q is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Activity:	Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[PIM2_HUMAN] Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression, the regulation of cap-dependent protein translation and through survival signaling by phosphorylation of a pro-apoptotic protein, BAD. Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase transcriptional activity. The stabilization of MYC exerted by PIM2 might explain partly the strong synergism between these 2 oncogenes in tumorigenesis. Regulates cap-dependent protein translation in a mammalian target of rapamycin complex 1 (mTORC1)-independent manner and in parallel to the PI3K-Akt pathway. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti-apoptotic protein Bcl-X(L)/BCL2L1. Promotes cell survival in response to a variety of proliferative signals via positive regulation of the I-kappa-B kinase/NF-kappa-B cascade; this process requires phosphorylation of MAP3K8/COT. Isoform 1 is less active in this respect. Promotes growth factor-independent proliferation by phosphorylation of cell cycle factors such as CDKN1A and CDKN1B. Involved in the positive regulation of chondrocyte survival and autophagy in the epiphyseal growth plate.^[1] ^[2] ^[3]

Publication Abstract from PubMed

PIM kinases are implicated in variety of cancers by promoting cell survival and proliferation and are targets of interest for therapeutic intervention. We have identified a low-nanomolar pan-PIM inhibitor (PIM1/2/3 potency 5:14:2nM) using structure based modeling. The crystal structure of this compound with PIM1 confirmed the predicted binding mode and protein-ligand interactions except those in the acidic ribose pocket. We show the SAR suggesting the importance of having a hydrogen bond donor in this pocket for inhibiting PIM2; however, this interaction is not important for inhibiting PIM1 or PIM3. In addition, we report the discovery of a new class of PIM inhibitors by using computational de novo design tool implemented in MOE software (Chemical Computing Group). These inhibitors have a different interaction profile.

Structure-based design of low-nanomolar PIM kinase inhibitors.,Ishchenko A, Zhang L, Le Brazidec JY, Fan J, Chong JH, Hingway A, Raditsis A, Singh L, Elenbaas B, Hong VS, Marcotte D, Silvian L, Enyedy I, Chao J Bioorg Med Chem Lett. 2015 Feb 1;25(3):474-80. doi: 10.1016/j.bmcl.2014.12.041., Epub 2014 Dec 19. PMID:25575657^[4]

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

References

↑ 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
↑ Gong J, Wang J, Ren K, Liu C, Li B, Shi Y. Serine/threonine kinase Pim-2 promotes liver tumorigenesis induction through mediating survival and preventing apoptosis of liver cell. J Surg Res. 2009 May 1;153(1):17-22. doi: 10.1016/j.jss.2008.03.033. Epub 2008, Apr 22. PMID:18675992 doi:http://dx.doi.org/10.1016/j.jss.2008.03.033
↑ Wang Z, Zhang Y, Gu JJ, Davitt C, Reeves R, Magnuson NS. Pim-2 phosphorylation of p21(Cip1/WAF1) enhances its stability and inhibits cell proliferation in HCT116 cells. Int J Biochem Cell Biol. 2010 Jun;42(6):1030-8. doi:, 10.1016/j.biocel.2010.03.012. Epub 2010 Mar 20. PMID:20307683 doi:http://dx.doi.org/10.1016/j.biocel.2010.03.012
↑ Ishchenko A, Zhang L, Le Brazidec JY, Fan J, Chong JH, Hingway A, Raditsis A, Singh L, Elenbaas B, Hong VS, Marcotte D, Silvian L, Enyedy I, Chao J. Structure-based design of low-nanomolar PIM kinase inhibitors. Bioorg Med Chem Lett. 2015 Feb 1;25(3):474-80. doi: 10.1016/j.bmcl.2014.12.041., Epub 2014 Dec 19. PMID:25575657 doi:http://dx.doi.org/10.1016/j.bmcl.2014.12.041

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4x7q"

Categories: Non-specific serine/threonine protein kinase | Marcotte, D J | Silvian, L F | Transferase-transferase inhibitor complex

@@ Line 1: / Line 1: @@
 ==PIM2 kinase in complex with Compound 1s==
 <StructureSection load='4x7q' size='340' side='right' caption='[[4x7q]], [[Resolution|resolution]] 2.33&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3YR:2-(2,6-DIFLUOROPHENYL)-N-{4-[(3S)-PYRROLIDIN-3-YLOXY]PYRIDIN-3-YL}-1,3-THIAZOLE-4-CARBOXAMIDE'>3YR</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=4x7q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x7q OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4x7q RCSB], [http://www.ebi.ac.uk/pdbsum/4x7q PDBsum]</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=4x7q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x7q OCA], [http://pdbe.org/4x7q PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4x7q RCSB], [http://www.ebi.ac.uk/pdbsum/4x7q PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4x7q ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4x7q" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4x7q

From Proteopedia

Revision as of 00:20, 26 January 2017

PIM2 kinase in complex with Compound 1s

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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