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[[Image:2w96.png|left|200px]]


{{STRUCTURE_2w96| PDB=2w96 | SCENE= }}
==Crystal Structure of CDK4 in complex with a D-type cyclin==
<StructureSection load='2w96' size='340' side='right'caption='[[2w96]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2w96]] 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=2W96 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2W96 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</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=2w96 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2w96 OCA], [https://pdbe.org/2w96 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2w96 RCSB], [https://www.ebi.ac.uk/pdbsum/2w96 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2w96 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/CDK4_HUMAN CDK4_HUMAN] Defects in CDK4 are a cause of susceptibility to cutaneous malignant melanoma type 3 (CMM3) [MIM:[https://omim.org/entry/609048 609048]. Malignant melanoma is a malignant neoplasm of melanocytes, arising de novo or from a pre-existing benign nevus, which occurs most often in the skin but also may involve other sites.<ref>PMID:7652577</ref> <ref>PMID:8528263</ref> <ref>PMID:9311594</ref> <ref>PMID:9425228</ref>
== Function ==
[https://www.uniprot.org/uniprot/CDK4_HUMAN CDK4_HUMAN] Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G(1)/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complexes and the subsequent transcription of E2F target genes which are responsible for the progression through the G(1) phase. Hypophosphorylates RB1 in early G(1) phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Also phosphorylates SMAD3 in a cell-cycle-dependent manner and represses its transcriptional activity. Component of the ternary complex, cyclin D/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex.<ref>PMID:9003781</ref> <ref>PMID:15241418</ref> <ref>PMID:18827403</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/w9/2w96_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=2w96 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The cyclin D1-cyclin-dependent kinase 4 (CDK4) complex is a key regulator of the transition through the G(1) phase of the cell cycle. Among the cyclin/CDKs, CDK4 and cyclin D1 are the most frequently activated by somatic genetic alterations in multiple tumor types. Thus, aberrant regulation of the CDK4/cyclin D1 pathway plays an essential role in oncogenesis; hence, CDK4 is a genetically validated therapeutic target. Although X-ray crystallographic structures have been determined for various CDK/cyclin complexes, CDK4/cyclin D1 has remained highly refractory to structure determination. Here, we report the crystal structure of CDK4 in complex with cyclin D1 at a resolution of 2.3 A. Although CDK4 is bound to cyclin D1 and has a phosphorylated T-loop, CDK4 is in an inactive conformation and the conformation of the heterodimer diverges from the previously known CDK/cyclin binary complexes, which suggests a unique mechanism for the process of CDK4 regulation and activation.


===CRYSTAL STRUCTURE OF CDK4 IN COMPLEX WITH A D-TYPE CYCLIN===
Crystal structure of human CDK4 in complex with a D-type cyclin.,Day PJ, Cleasby A, Tickle IJ, O'Reilly M, Coyle JE, Holding FP, McMenamin RL, Yon J, Chopra R, Lengauer C, Jhoti H Proc Natl Acad Sci U S A. 2009 Feb 23. PMID:19237565<ref>PMID:19237565</ref>


{{ABSTRACT_PUBMED_19237565}}
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 
</div>
==About this Structure==
<div class="pdbe-citations 2w96" style="background-color:#fffaf0;"></div>
[[2w96]] is a 2 chain structure of [[Cyclin]] and [[Cyclin Dependent Kinase-4]] with sequence 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=2W96 OCA].


==See Also==
==See Also==
*[[Cyclin|Cyclin]]
*[[Cyclin 3D structures|Cyclin 3D structures]]
*[[Cyclin Dependent Kinase-4|Cyclin Dependent Kinase-4]]
*[[Cyclin Dependent Kinase-4|Cyclin Dependent Kinase-4]]
 
*[[Cyclin-dependent kinase 3D structures|Cyclin-dependent kinase 3D structures]]
==Reference==
== References ==
<ref group="xtra">PMID:019237565</ref><references group="xtra"/>
<references/>
[[Category: Cyclin-dependent kinase]]
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Chopra, R.]]
[[Category: Large Structures]]
[[Category: Cleasby, A.]]
[[Category: Chopra R]]
[[Category: Coyle, J E.]]
[[Category: Cleasby A]]
[[Category: Day, P J.]]
[[Category: Coyle JE]]
[[Category: Holding, F P.]]
[[Category: Day PJ]]
[[Category: Jhoti, H.]]
[[Category: Holding FP]]
[[Category: Lengauer, C.]]
[[Category: Jhoti H]]
[[Category: Mcmenamin, R L.]]
[[Category: Lengauer C]]
[[Category: Reilly, M O.]]
[[Category: McMenamin RL]]
[[Category: Tickle, I J.]]
[[Category: Reilly MO]]
[[Category: Yon, J.]]
[[Category: Tickle IJ]]
[[Category: Atp-binding]]
[[Category: Yon J]]
[[Category: Cell cycle]]
[[Category: Cell division]]
[[Category: Cyclin]]
[[Category: Cyclin dependent kinase]]
[[Category: Disease mutation]]
[[Category: Drug desgn]]
[[Category: Kinase]]
[[Category: Nucleotide-binding]]
[[Category: Oncology]]
[[Category: Phosphoprotein]]
[[Category: Proto-oncogene]]
[[Category: Serine/threonine-protein kinase]]
[[Category: Transferase]]
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