2c3i

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Current revision (14:04, 13 December 2023) (edit) (undo)
 
(10 intermediate revisions not shown.)
Line 1: Line 1:
-
{{Seed}}
 
-
[[Image:2c3i.png|left|200px]]
 
-
<!--
+
==CRYSTAL STRUCTURE OF HUMAN PIM1 IN COMPLEX WITH IMIDAZOPYRIDAZIN I==
-
The line below this paragraph, containing "STRUCTURE_2c3i", creates the "Structure Box" on the page.
+
<StructureSection load='2c3i' size='340' side='right'caption='[[2c3i]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
-
You may change the PDB parameter (which sets the PDB file loaded into the applet)
+
== Structural highlights ==
-
or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+
<table><tr><td colspan='2'>[[2c3i]] is a 2 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=2C3I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2C3I FirstGlance]. <br>
-
or leave the SCENE parameter empty for the default display.
+
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
-
-->
+
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IYZ:1-(3-{6-[(CYCLOPROPYLMETHYL)AMINO]IMIDAZO[1,2-B]PYRIDAZIN-3-YL}PHENYL)ETHANONE'>IYZ</scene></td></tr>
-
{{STRUCTURE_2c3i| PDB=2c3i | SCENE= }}
+
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2c3i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2c3i OCA], [https://pdbe.org/2c3i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2c3i RCSB], [https://www.ebi.ac.uk/pdbsum/2c3i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2c3i ProSAT]</span></td></tr>
 +
</table>
 +
== Function ==
 +
[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>
 +
== Evolutionary Conservation ==
 +
[[Image:Consurf_key_small.gif|200px|right]]
 +
Check<jmol>
 +
<jmolCheckbox>
 +
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/c3/2c3i_consurf.spt"</scriptWhenChecked>
 +
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
 +
<text>to colour the structure by Evolutionary Conservation</text>
 +
</jmolCheckbox>
 +
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2c3i ConSurf].
 +
<div style="clear:both"></div>
 +
<div style="background-color:#fffaf0;">
 +
== Publication Abstract from PubMed ==
 +
Much attention has recently been focused on PIM kinases as potential targets for the treatment of hematopoietic malignancies and some solid cancers. Using protein stability shift assays, we identified a family of imidazo[1,2-b]pyridazines to specifically interact with and inhibit PIM kinases with low nanomolar potency. The high-resolution crystal structure of a PIM1 inhibitor complex revealed that imidazo[1,2-b]pyridazines surprisingly interact with the NH(2)-terminal lobe helix alphaC rather than with the kinase hinge region. Thus, the identified inhibitors are ATP competitive but not ATP mimetic compounds, explaining their enhanced selectivity with respect to conventional type I kinase inhibitors. One of the identified imidazo[1,2-b]pyridazines (K00135) was further tested in several hematopoietic cellular systems. First, K00135 dose-dependently impaired survival of murine Ba/F3 cells that have been rendered cytokine independent by overexpression of human PIMs. Second, K00135 impaired survival and clonogenic growth of a panel of human acute leukemia cells. Third, exposure of K00135 significantly suppressed in vitro growth of leukemic blasts from five acute myelogenous leukemia patients but not of normal umbilical cord blood mononuclear cells. In vitro kinase assays and immunoblotting using lysates from human MV4;11 leukemic cells showed inhibition of phosphorylation of known PIM downstream targets, such as BAD and eukaryotic translation initiation factor 4E-binding protein 1, by K00135. Taken together, we report a family of small molecules that selectively interact and block PIM kinases and could serve as a lead to develop new targeted antileukemic therapeutics.
-
===CRYSTAL STRUCTURE OF HUMAN PIM1 IN COMPLEX WITH IMIDAZOPYRIDAZIN I===
+
Structural analysis identifies imidazo[1,2-b]pyridazines as PIM kinase inhibitors with in vitro antileukemic activity.,Pogacic V, Bullock AN, Fedorov O, Filippakopoulos P, Gasser C, Biondi A, Meyer-Monard S, Knapp S, Schwaller J Cancer Res. 2007 Jul 15;67(14):6916-24. PMID:17638903<ref>PMID:17638903</ref>
 +
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 +
</div>
 +
<div class="pdbe-citations 2c3i" style="background-color:#fffaf0;"></div>
-
<!--
+
==See Also==
-
The line below this paragraph, {{ABSTRACT_PUBMED_17638903}}, adds the Publication Abstract to the page
+
*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
-
(as it appears on PubMed at http://www.pubmed.gov), where 17638903 is the PubMed ID number.
+
*[[3D structures of pim-1|3D structures of pim-1]]
-
-->
+
== References ==
-
{{ABSTRACT_PUBMED_17638903}}
+
<references/>
-
 
+
__TOC__
-
==About this Structure==
+
</StructureSection>
-
2C3I is a 2 chains structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2C3I OCA].
+
-
 
+
-
==Reference==
+
-
<ref group="xtra">PMID:17638903</ref><references group="xtra"/>
+
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
-
[[Category: Non-specific serine/threonine protein kinase]]
+
[[Category: Large Structures]]
-
[[Category: Arrowsmith, C.]]
+
[[Category: Arrowsmith C]]
-
[[Category: Bullock, A.]]
+
[[Category: Bullock A]]
-
[[Category: Debreczeni, J.]]
+
[[Category: Debreczeni J]]
-
[[Category: Delft, F Von.]]
+
[[Category: Edwards A]]
-
[[Category: Edwards, A.]]
+
[[Category: Guo K]]
-
[[Category: Guo, K.]]
+
[[Category: Knapp S]]
-
[[Category: Knapp, S.]]
+
[[Category: Philippakopoulos P]]
-
[[Category: Philippakopoulos, P.]]
+
[[Category: Sundstrom M]]
-
[[Category: Sundstrom, M.]]
+
[[Category: Weigelt J]]
-
[[Category: Weigelt, J.]]
+
[[Category: Von Delft F]]
-
[[Category: Atp-binding]]
+
-
[[Category: Cancer]]
+
-
[[Category: Complex transferase/peptide]]
+
-
[[Category: Kinase]]
+
-
[[Category: Leukemia]]
+
-
[[Category: Nuclear protein]]
+
-
[[Category: Nucleotide-binding]]
+
-
[[Category: Phosphorylation]]
+
-
[[Category: Pim1]]
+
-
[[Category: Proto- oncogene]]
+
-
[[Category: Serine/threonine-protein kinase]]
+
-
[[Category: Transferase]]
+
-
[[Category: Transferase/peptide]]
+
-
 
+
-
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 22 11:26:35 2009''
+

Current revision

CRYSTAL STRUCTURE OF HUMAN PIM1 IN COMPLEX WITH IMIDAZOPYRIDAZIN I

PDB ID 2c3i

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2c3i"
Personal tools