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5kzi

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Revision as of 06:37, 5 August 2020

Crystal structure of human Pim-1 kinase in complex with an imidazopyridazine inhibitor.

Structural highlights

5kzi is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	PIM1 (HUMAN)
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

High levels of Pim expression have been implicated in several hematopoietic and solid tumor cancers, suggesting that inhibition of Pim signaling could provide patients with therapeutic benefit. Herein, we describe our progress towards this goal using a screening hit (rac-1) as a starting point. Modification of the indazole ring resulted in the discovery of a series of imidazopyridazine-based Pim inhibitors exemplified by compound 22m, which was found to be a subnanomolar inhibitor of the Pim-1 and Pim-2 isoforms (IC50 values of 0.024nM and 0.095nM, respectively) and to potently inhibit the phosphorylation of BAD in a cell line that expresses high levels of all Pim isoforms, KMS-12-BM (IC50=28nM). Profiling of Pim-1 and Pim-2 expression levels in a panel of multiple myeloma cell lines and correlation of these data with the potency of compound 22m in a proliferation assay suggests that Pim-2 inhibition would be advantageous for this indication.

Discovery of imidazopyridazines as potent Pim-1/2 kinase inhibitors.,Wurz RP, Sastri C, D'Amico DC, Herberich B, Jackson CL, Pettus LH, Tasker AS, Wu B, Guerrero N, Lipford JR, Winston JT, Yang Y, Wang P, Nguyen Y, Andrews KL, Huang X, Lee MR, Mohr C, Zhang JD, Reid DL, Xu Y, Zhou Y, Wang HL Bioorg Med Chem Lett. 2016 Oct 1. pii: S0960-894X(16)31016-2. doi:, 10.1016/j.bmcl.2016.09.067. PMID:27769621^[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
↑ Wurz RP, Sastri C, D'Amico DC, Herberich B, Jackson CL, Pettus LH, Tasker AS, Wu B, Guerrero N, Lipford JR, Winston JT, Yang Y, Wang P, Nguyen Y, Andrews KL, Huang X, Lee MR, Mohr C, Zhang JD, Reid DL, Xu Y, Zhou Y, Wang HL. Discovery of imidazopyridazines as potent Pim-1/2 kinase inhibitors. Bioorg Med Chem Lett. 2016 Oct 1. pii: S0960-894X(16)31016-2. doi:, 10.1016/j.bmcl.2016.09.067. PMID:27769621 doi:http://dx.doi.org/10.1016/j.bmcl.2016.09.067

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/5kzi"

@@ Line 1: / Line 1: @@
 ==Crystal structure of human Pim-1 kinase in complex with an imidazopyridazine inhibitor.==
-<StructureSection load='5kzi' size='340' side='right' caption='[[5kzi]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
+<StructureSection load='5kzi' size='340' side='right'caption='[[5kzi]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5kzi]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KZI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5KZI FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5kzi]] is a 1 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=5KZI OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5KZI FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6YN:~{N}-[4-[(3~{S})-3-AZANYLPIPERIDIN-1-YL]PYRIDIN-3-YL]-2-[2,6-BIS(FLUORANYL)PHENYL]IMIDAZO[1,5-B]PYRIDAZIN-7-AMINE'>6YN</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6YN:~{N}-[4-[(3~{S})-3-AZANYLPIPERIDIN-1-YL]PYRIDIN-3-YL]-2-[2,6-BIS(FLUORANYL)PHENYL]IMIDAZO[1,5-B]PYRIDAZIN-7-AMINE'>6YN</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PIM1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5kzi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kzi OCA], [http://pdbe.org/5kzi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5kzi RCSB], [http://www.ebi.ac.uk/pdbsum/5kzi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5kzi 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=5kzi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kzi OCA], [http://pdbe.org/5kzi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5kzi RCSB], [http://www.ebi.ac.uk/pdbsum/5kzi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5kzi ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 23: / Line 24: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Non-specific serine/threonine protein kinase]]
 [[Category: Mohr, C]]

5kzi

From Proteopedia

Revision as of 06:37, 5 August 2020

Crystal structure of human Pim-1 kinase in complex with an imidazopyridazine inhibitor.

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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