Proteopedia

4ez5: Difference between revisions

← Older edit
No edit summary
No edit summary
 
(2 intermediate revisions by the same user not shown)
Line 1: Line 1:


==CDK6 (monomeric) in complex with inhibitor==
==CDK6 (monomeric) in complex with inhibitor==
<StructureSection load='4ez5' size='340' side='right' caption='[[4ez5]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
<StructureSection load='4ez5' size='340' side='right'caption='[[4ez5]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4ez5]] 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=4EZ5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EZ5 FirstGlance]. <br>
<table><tr><td colspan='2'>[[4ez5]] 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=4EZ5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4EZ5 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0RS:{5-[4-(DIMETHYLAMINO)PIPERIDIN-1-YL]-1H-IMIDAZO[4,5-B]PYRIDIN-2-YL}[2-(ISOQUINOLIN-4-YL)PYRIDIN-4-YL]METHANONE'>0RS</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3nup|3nup]], [[3nux|3nux]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0RS:{5-[4-(DIMETHYLAMINO)PIPERIDIN-1-YL]-1H-IMIDAZO[4,5-B]PYRIDIN-2-YL}[2-(ISOQUINOLIN-4-YL)PYRIDIN-4-YL]METHANONE'>0RS</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CDK6, CDKN6 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4ez5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ez5 OCA], [https://pdbe.org/4ez5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ez5 RCSB], [https://www.ebi.ac.uk/pdbsum/4ez5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ez5 ProSAT]</span></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cyclin-dependent_kinase Cyclin-dependent kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.22 2.7.11.22] </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=4ez5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ez5 OCA], [http://pdbe.org/4ez5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ez5 RCSB], [http://www.ebi.ac.uk/pdbsum/4ez5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ez5 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/CDK6_HUMAN CDK6_HUMAN]] Serine/threonine-protein kinase involved in the control of the cell cycle and differentiation; promotes G1/S transition. Phosphorylates pRB/RB1 and NPM1. Interacts with D-type G1 cyclins during interphase at G1 to form a pRB/RB1 kinase and controls the entrance into the cell cycle. Involved in initiation and maintenance of cell cycle exit during cell differentiation; prevents cell proliferation and regulates negatively cell differentiation, but is required for the proliferation of specific cell types (e.g. erythroid and hematopoietic cells). Essential for cell proliferation within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Required during thymocyte development. Promotes the production of newborn neurons, probably by modulating G1 length. Promotes, at least in astrocytes, changes in patterns of gene expression, changes in the actin cytoskeleton including loss of stress fibers, and enhanced motility during cell differentiation. Prevents myeloid differentiation by interfering with RUNX1 and reducing its transcription transactivation activity, but promotes proliferation of normal myeloid progenitors. Delays senescence. Promotes the proliferation of beta-cells in pancreatic islets of Langerhans.<ref>PMID:8114739</ref> <ref>PMID:12833137</ref> <ref>PMID:14985467</ref> <ref>PMID:15254224</ref> <ref>PMID:15809340</ref> <ref>PMID:17431401</ref> <ref>PMID:17420273</ref> <ref>PMID:20668294</ref> <ref>PMID:20333249</ref> 
[https://www.uniprot.org/uniprot/CDK6_HUMAN CDK6_HUMAN] Serine/threonine-protein kinase involved in the control of the cell cycle and differentiation; promotes G1/S transition. Phosphorylates pRB/RB1 and NPM1. Interacts with D-type G1 cyclins during interphase at G1 to form a pRB/RB1 kinase and controls the entrance into the cell cycle. Involved in initiation and maintenance of cell cycle exit during cell differentiation; prevents cell proliferation and regulates negatively cell differentiation, but is required for the proliferation of specific cell types (e.g. erythroid and hematopoietic cells). Essential for cell proliferation within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Required during thymocyte development. Promotes the production of newborn neurons, probably by modulating G1 length. Promotes, at least in astrocytes, changes in patterns of gene expression, changes in the actin cytoskeleton including loss of stress fibers, and enhanced motility during cell differentiation. Prevents myeloid differentiation by interfering with RUNX1 and reducing its transcription transactivation activity, but promotes proliferation of normal myeloid progenitors. Delays senescence. Promotes the proliferation of beta-cells in pancreatic islets of Langerhans.<ref>PMID:8114739</ref> <ref>PMID:12833137</ref> <ref>PMID:14985467</ref> <ref>PMID:15254224</ref> <ref>PMID:15809340</ref> <ref>PMID:17431401</ref> <ref>PMID:17420273</ref> <ref>PMID:20668294</ref> <ref>PMID:20333249</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Herein, we describe the discovery of potent and highly selective inhibitors of both CDK4 and CDK6 via structure-guided optimization of a fragment-based screening hit. CDK6 X-ray crystallography and pharmacokinetic data steered efforts in identifying compound 6, which showed &gt;1000-fold selectivity for CDK4 over CDKs 1 and 2 in an enzymatic assay. Furthermore, 6 demonstrated in vivo inhibition of pRb-phosphorylation and oral efficacy in a Jeko-1 mouse xenograft model.
 
Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors.,Cho YS, Angove H, Brain C, Chen CH, Cheng H, Cheng R, Chopra R, Chung K, Congreve M, Dagostin C, Davis DJ, Feltell R, Giraldes J, Hiscock SD, Kim S, Kovats S, Lagu B, Lewry K, Loo A, Lu Y, Luzzio M, Maniara W, McMenamin R, Mortenson PN, Benning R, O'Reilly M, Rees DC, Shen J, Smith T, Wang Y, Williams G, Woolford AJ, Wrona W, Xu M, Yang F, Howard S ACS Med Chem Lett. 2012 May 17;3(6):445-9. doi: 10.1021/ml200241a. eCollection, 2012 Jun 14. PMID:24900493<ref>PMID:24900493</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4ez5" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Cyclin-dependent kinase|Cyclin-dependent kinase]]
*[[Cyclin-dependent kinase 3D structures|Cyclin-dependent kinase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Cyclin-dependent kinase]]
[[Category: Homo sapiens]]
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Chopra, R]]
[[Category: Chopra R]]
[[Category: Xu, M]]
[[Category: Xu M]]
[[Category: Atp binding]]
[[Category: Protein kinase]]
[[Category: Transferase-transferase inhibitor complex]]

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
Retrieved from "https://proteopedia.openfox.io/w/4ez5"