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==Crystal structure of CDK4/cyclin D3==
==Crystal structure of CDK4/cyclin D3==
<StructureSection load='3g33' size='340' side='right' caption='[[3g33]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
<StructureSection load='3g33' size='340' side='right'caption='[[3g33]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3g33]] is a 4 chain structure 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=3G33 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3G33 FirstGlance]. <br>
<table><tr><td colspan='2'>[[3g33]] is a 4 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=3G33 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3G33 FirstGlance]. <br>
</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CDK4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]), CCND3, hCG_16683 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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]] 3&#8491;</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'>[https://proteopedia.org/fgij/fg.htm?mol=3g33 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3g33 OCA], [https://pdbe.org/3g33 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3g33 RCSB], [https://www.ebi.ac.uk/pdbsum/3g33 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3g33 ProSAT]</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=3g33 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3g33 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3g33 RCSB], [http://www.ebi.ac.uk/pdbsum/3g33 PDBsum]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/CDK4_HUMAN CDK4_HUMAN]] Defects in CDK4 are a cause of susceptibility to cutaneous malignant melanoma type 3 (CMM3) [MIM:[http://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>
[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 ==
== Function ==
[[http://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> [[http://www.uniprot.org/uniprot/CCND3_HUMAN CCND3_HUMAN]] Regulatory component of the cyclin D3-CDK4 (DC) complex that phosphorylates and inhibits members of the retinoblastoma (RB) protein family including RB1 and regulates the cell-cycle during G(1)/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complex 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 substrate for SMAD3, phosphorylating SMAD3 in a cell-cycle-dependent manner and repressing its transcriptional activity. Component of the ternary complex, cyclin D3/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex.<ref>PMID:15358120</ref> 
[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 ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
Check<jmol>
   <jmolCheckbox>
   <jmolCheckbox>
     <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/g3/3g33_consurf.spt"</scriptWhenChecked>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/g3/3g33_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
   </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/chain_selection.php?pdb_ID=2ata ConSurf].
</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=3g33 ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Cyclin-dependent kinase 4 (CDK4)/cyclin D complexes are expressed early in the G(1) phase of the cell cycle and stimulate the expression of genes required for G(1) progression by phosphorylation of the product of the retinoblastoma gene, pRb. To elaborate the molecular pathway of CDK4 activation and substrate selection we have determined the structure of nonphosphorylated CDK4/cyclin D3. This structure of an authentic CDK/cyclin complex shows that cyclin binding may not be sufficient to drive the CDK active site toward an active conformation. Phosphorylated CDK4/cyclin D3 is active as a pRb kinase and is susceptible to inhibition by p27(Kip1). Unlike CDK2/cyclin A, CDK4/cyclin D3 can be inactivated by treatment with lambda-phosphatase, implying that phosphorylated T172 is accessible to a generic phosphatase while bound to a cyclin. Taken together, these results suggest that the structural mechanism of CDK4/cyclin D3 activation differs markedly from that of previously studied CDK/cyclin complexes.
The structure of CDK4/cyclin D3 has implications for models of CDK activation.,Takaki T, Echalier A, Brown NR, Hunt T, Endicott JA, Noble ME Proc Natl Acad Sci U S A. 2009 Feb 23. PMID:19237555<ref>PMID:19237555</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>


==See Also==
==See Also==
*[[Cyclin|Cyclin]]
*[[Cyclin 3D structures|Cyclin 3D structures]]
*[[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: Homo sapiens]]
[[Category: Brown, N R]]
[[Category: Large Structures]]
[[Category: Echalier, A]]
[[Category: Brown NR]]
[[Category: Endicott, J A]]
[[Category: Echalier A]]
[[Category: Hunt, T]]
[[Category: Endicott JA]]
[[Category: Noble, M E.M]]
[[Category: Hunt T]]
[[Category: Takaki, T]]
[[Category: Noble MEM]]
[[Category: Atp-binding]]
[[Category: Takaki T]]
[[Category: Cell cycle]]
[[Category: Cell division]]
[[Category: Cyclin]]
[[Category: Disease mutation]]
[[Category: Kinase]]
[[Category: Nucleotide-binding]]
[[Category: Phosphoprotein]]
[[Category: Phosphorylation]]
[[Category: Proto-oncogene]]
[[Category: Ser/thr protein kinase]]
[[Category: Serine/threonine-protein kinase]]
[[Category: Transferase]]
Retrieved from "https://proteopedia.org/3g33"