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1xo2

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Revision as of 10:10, 6 January 2021

Crystal structure of a human cyclin-dependent kinase 6 complex with a flavonol inhibitor, fisetin

Structural highlights

1xo2 is a 2 chain structure with sequence from Human and Herpesvirus saimiri. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	1jow
Gene:	72, ECLF2 (Herpesvirus saimiri), CDK6 (HUMAN)
Activity:	Transferase, with EC number 2.7.11.8, 2.7.11.9, 2.7.11.10, 2.7.11.11, 2.7.11.12, 2.7.11.13, 2.7.11.21, 2.7.11.22, 2.7.11.24, 2.7.11.25, 2.7.11.30 and 2.7.12.1 2.7.11.1, 2.7.11.8, 2.7.11.9, 2.7.11.10, 2.7.11.11, 2.7.11.12, 2.7.11.13, 2.7.11.21, 2.7.11.22, 2.7.11.24, 2.7.11.25, 2.7.11.30 and 2.7.12.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[CGH2_SHV21] May be highly relevant to the process of cellular transformation and rapid T-cell proliferation effected by HVS during latent infections of T-cells in susceptible hosts. [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.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Cyclin-dependent kinases (CDKs) play a central role in cell cycle control, apoptosis, transcription, and neuronal functions. They are important targets for the design of drugs with antimitotic or antineurodegenerative effects. CDK4 and CDK6 form a subfamily among the CDKs in mammalian cells, as defined by sequence similarities. Compared to CDK2 and CDK5, structural information on CDK4 and CDK6 is sparse. We describe here the crystal structure of human CDK6 in complex with a viral cyclin and a flavonol inhibitor, fisetin. Fisetin binds to the active form of CDK6, forming hydrogen bonds with the side chains of residues in the binding pocket that undergo large conformational changes during CDK activation by cyclin binding. The 4-keto group and the 3-hydroxyl group of fisetin are hydrogen bonded with the backbone in the hinge region between the N-terminal and C-terminal kinase domain, as has been observed for many CDK inhibitors. However, CDK2 and HCK kinase in complex with other flavone inhibitors such as quercetin and flavopiridol showed a different binding mode with the inhibitor rotated by about 180 degrees. The structural information of the CDK6-fisetin complex is correlated with the binding affinities of different flavone inhibitors for CDK6. This complex structure is the first description of an inhibitor complex with a kinase from the CDK4/6 subfamily and can provide a basis for selecting and designing inhibitor compounds with higher affinities and specificities.

Crystal structure of a human cyclin-dependent kinase 6 complex with a flavonol inhibitor, fisetin.,Lu H, Chang DJ, Baratte B, Meijer L, Schulze-Gahmen U J Med Chem. 2005 Feb 10;48(3):737-43. PMID:15689157^[10]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Meyerson M, Harlow E. Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Mol Cell Biol. 1994 Mar;14(3):2077-86. PMID:8114739
↑ Matushansky I, Radparvar F, Skoultchi AI. CDK6 blocks differentiation: coupling cell proliferation to the block to differentiation in leukemic cells. Oncogene. 2003 Jul 3;22(27):4143-9. PMID:12833137 doi:10.1038/sj.onc.1206484
↑ Lucas JJ, Domenico J, Gelfand EW. Cyclin-dependent kinase 6 inhibits proliferation of human mammary epithelial cells. Mol Cancer Res. 2004 Feb;2(2):105-14. PMID:14985467
↑ Ogasawara T, Kawaguchi H, Jinno S, Hoshi K, Itaka K, Takato T, Nakamura K, Okayama H. Bone morphogenetic protein 2-induced osteoblast differentiation requires Smad-mediated down-regulation of Cdk6. Mol Cell Biol. 2004 Aug;24(15):6560-8. PMID:15254224 doi:10.1128/MCB.24.15.6560-6568.2004
↑ Takaki T, Fukasawa K, Suzuki-Takahashi I, Semba K, Kitagawa M, Taya Y, Hirai H. Preferences for phosphorylation sites in the retinoblastoma protein of D-type cyclin-dependent kinases, Cdk4 and Cdk6, in vitro. J Biochem. 2005 Mar;137(3):381-6. PMID:15809340 doi:10.1093/jb/mvi050
↑ Fujimoto T, Anderson K, Jacobsen SE, Nishikawa SI, Nerlov C. Cdk6 blocks myeloid differentiation by interfering with Runx1 DNA binding and Runx1-C/EBPalpha interaction. EMBO J. 2007 May 2;26(9):2361-70. Epub 2007 Apr 12. PMID:17431401 doi:10.1038/sj.emboj.7601675
↑ Ruas M, Gregory F, Jones R, Poolman R, Starborg M, Rowe J, Brookes S, Peters G. CDK4 and CDK6 delay senescence by kinase-dependent and p16INK4a-independent mechanisms. Mol Cell Biol. 2007 Jun;27(12):4273-82. Epub 2007 Apr 9. PMID:17420273 doi:10.1128/MCB.02286-06
↑ Fiaschi-Taesch NM, Salim F, Kleinberger J, Troxell R, Cozar-Castellano I, Selk K, Cherok E, Takane KK, Scott DK, Stewart AF. Induction of human beta-cell proliferation and engraftment using a single G1/S regulatory molecule, cdk6. Diabetes. 2010 Aug;59(8):1926-36. doi: 10.2337/db09-1776. PMID:20668294 doi:10.2337/db09-1776
↑ Sarek G, Jarviluoma A, Moore HM, Tojkander S, Vartia S, Biberfeld P, Laiho M, Ojala PM. Nucleophosmin phosphorylation by v-cyclin-CDK6 controls KSHV latency. PLoS Pathog. 2010 Mar 19;6(3):e1000818. doi: 10.1371/journal.ppat.1000818. PMID:20333249 doi:10.1371/journal.ppat.1000818
↑ Lu H, Chang DJ, Baratte B, Meijer L, Schulze-Gahmen U. Crystal structure of a human cyclin-dependent kinase 6 complex with a flavonol inhibitor, fisetin. J Med Chem. 2005 Feb 10;48(3):737-43. PMID:15689157 doi:10.1021/jm049353p

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1xo2"

@@ Line 1: / Line 1: @@
 ==Crystal structure of a human cyclin-dependent kinase 6 complex with a flavonol inhibitor, fisetin==
-<StructureSection load='1xo2' size='340' side='right' caption='[[1xo2]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
+<StructureSection load='1xo2' size='340' side='right'caption='[[1xo2]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1xo2]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Herpesvirus_saimiri Herpesvirus saimiri]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XO2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1XO2 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1xo2]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Herpesvirus_saimiri Herpesvirus saimiri]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XO2 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=1XO2 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FSE:3,7,3,4-TETRAHYDROXYFLAVONE'>FSE</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FSE:3,7,3,4-TETRAHYDROXYFLAVONE'>FSE</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1jow|1jow]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1jow|1jow]]</div></td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">72, ECLF2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10381 Herpesvirus saimiri]), CDK6 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1, 2.7.11.8, 2.7.11.9, 2.7.11.10, 2.7.11.11, 2.7.11.12, 2.7.11.13, 2.7.11.21, 2.7.11.22, 2.7.11.24, 2.7.11.25, 2.7.11.30 and 2.7.12.1 2.7.11.1, 2.7.11.8, 2.7.11.9, 2.7.11.10, 2.7.11.11, 2.7.11.12, 2.7.11.13, 2.7.11.21, 2.7.11.22, 2.7.11.24, 2.7.11.25, 2.7.11.30 and 2.7.12.1] </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=1xo2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xo2 OCA], [http://pdbe.org/1xo2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1xo2 RCSB], [http://www.ebi.ac.uk/pdbsum/1xo2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1xo2 ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=1xo2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xo2 OCA], [http://pdbe.org/1xo2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1xo2 RCSB], [http://www.ebi.ac.uk/pdbsum/1xo2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1xo2 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 33: / Line 33: @@
 ==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/>
@@ Line 41: / Line 41: @@
 [[Category: Herpesvirus saimiri]]
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Transferase]]
 [[Category: Baratte, B]]

1xo2

From Proteopedia

Revision as of 10:10, 6 January 2021

Crystal structure of a human cyclin-dependent kinase 6 complex with a flavonol inhibitor, fisetin

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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