4x7q: Difference between revisions
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''' | ==PIM2 kinase in complex with Compound 1s== | ||
<StructureSection load='4x7q' size='340' side='right' caption='[[4x7q]], [[Resolution|resolution]] 2.33Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4x7q]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4X7Q OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4X7Q FirstGlance]. <br> | |||
</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> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/PIM2_HUMAN 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.<ref>PMID:18593906</ref> <ref>PMID:18675992</ref> <ref>PMID:20307683</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:25575657</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
[[Category: | <references/> | ||
[[Category: Silvian, L | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: Non-specific serine/threonine protein kinase]] | |||
[[Category: Marcotte, D J]] | |||
[[Category: Silvian, L F]] | |||
[[Category: Transferase-transferase inhibitor complex]] | |||
Revision as of 14:47, 12 February 2015
PIM2 kinase in complex with Compound 1sPIM2 kinase in complex with Compound 1s
Structural highlights
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 PubMedPIM 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
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