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==Crystal structure of PIM1 in complex with a Pyrrolo-Pyrazinone inhibitor==
==Crystal structure of PIM1 in complex with a Pyrrolo-Pyrazinone inhibitor==
<StructureSection load='4bzo' size='340' side='right' caption='[[4bzo]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
<StructureSection load='4bzo' size='340' side='right'caption='[[4bzo]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4bzo]] 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=4BZO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BZO FirstGlance]. <br>
<table><tr><td colspan='2'>[[4bzo]] is a 1 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=4BZO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BZO FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=676:N-[(1S)-2-AMINO-1-PHENYLETHYL]-2-[(4S)-7-(2-FLUORO-4-PYRIDINYL)-1-OXO-1,2,3,4-TETRAHYDROPYRROLO[1,2-A]PYRAZIN-4-YL]ACETAMIDE'>676</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=676:N-[(1S)-2-AMINO-1-PHENYLETHYL]-2-[(4S)-7-(2-FLUORO-4-PYRIDINYL)-1-OXO-1,2,3,4-TETRAHYDROPYRROLO[1,2-A]PYRAZIN-4-YL]ACETAMIDE'>676</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</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=4bzo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bzo OCA], [https://pdbe.org/4bzo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bzo RCSB], [https://www.ebi.ac.uk/pdbsum/4bzo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bzo ProSAT]</span></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4bzn|4bzn]]</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=4bzo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bzo OCA], [http://pdbe.org/4bzo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4bzo RCSB], [http://www.ebi.ac.uk/pdbsum/4bzo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4bzo ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/PIM1_HUMAN 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.<ref>PMID:1825810</ref> <ref>PMID:10664448</ref> <ref>PMID:12431783</ref> <ref>PMID:15528381</ref> <ref>PMID:16356754</ref> <ref>PMID:18593906</ref> <ref>PMID:19749799</ref
[[https://www.uniprot.org/uniprot/PIM1_HUMAN 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.<ref>PMID:1825810</ref> <ref>PMID:10664448</ref> <ref>PMID:12431783</ref> <ref>PMID:15528381</ref> <ref>PMID:16356754</ref> <ref>PMID:18593906</ref> <ref>PMID:19749799</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
A novel series of PIM inhibitors was derived from a combined effort in natural product-inspired library generation and screening. The novel pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of PIM isoforms with IC50 values in the low micromolar range. The application of a rational optimization strategy, guided by the determination of the crystal structure of the complex in the kinase domain of PIM1 with compound 1, led to the discovery of compound 15a, which is a potent PIM kinases inhibitor exhibiting excellent selectivity against a large panel of kinases, representative of each family. The synthesis, structure-activity relationship studies, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Furthermore, the cellular activities including inhibition of cell growth and modulation of downstream targets are also described.
 
Discovery and optimization of pyrrolo[1,2-a]pyrazinones leads to novel and selective inhibitors of PIM kinases.,Casuscelli F, Ardini E, Avanzi N, Casale E, Cervi G, D'Anello M, Donati D, Faiardi D, Ferguson RD, Fogliatto G, Galvani A, Marsiglio A, Mirizzi DG, Montemartini M, Orrenius C, Papeo G, Piutti C, Salom B, Felder ER Bioorg Med Chem. 2013 Oct 2. pii: S0968-0896(13)00834-1. doi:, 10.1016/j.bmc.2013.09.054. PMID:24139169<ref>PMID:24139169</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4bzo" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Proto-oncogene serine/threonine-protein kinase|Proto-oncogene serine/threonine-protein kinase]]
*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
*[[Student Project 6 for UMass Chemistry 423 Spring 2015|Student Project 6 for UMass Chemistry 423 Spring 2015]]
*[[3D structures of pim-1|3D structures of pim-1]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Large Structures]]
[[Category: Anello, M D]]
[[Category: Ardini E]]
[[Category: Ardini, E]]
[[Category: Avanzi N]]
[[Category: Avanzi, N]]
[[Category: Casale E]]
[[Category: Casale, E]]
[[Category: Casuscelli F]]
[[Category: Casuscelli, F]]
[[Category: Cervi G]]
[[Category: Cervi, G]]
[[Category: D'Anello M]]
[[Category: Donati, D]]
[[Category: Donati D]]
[[Category: Faiardi, D]]
[[Category: Faiardi D]]
[[Category: Felder, E R]]
[[Category: Felder ER]]
[[Category: Ferguson, R D]]
[[Category: Ferguson RD]]
[[Category: Fogliatto, G]]
[[Category: Fogliatto G]]
[[Category: Galvani, A]]
[[Category: Galvani A]]
[[Category: Marsiglio, A]]
[[Category: Marsiglio A]]
[[Category: Mirizzi, D G]]
[[Category: Mirizzi DG]]
[[Category: Montemartini, M]]
[[Category: Montemartini M]]
[[Category: Orrenius, C]]
[[Category: Orrenius C]]
[[Category: Papeo, G]]
[[Category: Papeo G]]
[[Category: Piutti, C]]
[[Category: Piutti C]]
[[Category: Salom, B]]
[[Category: Salom B]]
[[Category: Atp binding]]
[[Category: Kinase inhibitor]]
[[Category: Pim1]]
[[Category: Transferase]]

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