1xo2: Difference between revisions

Revision as of 16:56, 21 February 2008

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

OverviewOverview

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.

About this StructureAbout this Structure

1XO2 is a Protein complex structure of sequences from Homo sapiens and Saimiriine herpesvirus 3 with as ligand. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Full crystallographic information is available from OCA.

ReferenceReference

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

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-[[Image:1xo2.gif|left|200px]]<br />
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 '''Crystal structure of a human cyclin-dependent kinase 6 complex with a flavonol inhibitor, fisetin'''<br />
 ==Overview==
-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.
+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.
 ==About this Structure==
-XO2 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Saimiriine_herpesvirus_3 Saimiriine herpesvirus 3] with FSE as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1XO2 OCA].
+XO2 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Saimiriine_herpesvirus_3 Saimiriine herpesvirus 3] with <scene name='pdbligand=FSE:'>FSE</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XO2 OCA].
 ==Reference==
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 [[Category: Saimiriine herpesvirus 3]]
 [[Category: Baratte, B.]]
-[[Category: Chang, D.J.]]
+[[Category: Chang, D J.]]
-[[Category: Lu, H.S.]]
+[[Category: Lu, H S.]]
 [[Category: Meijer, L.]]
 [[Category: Schulze-Gahmen, U.]]
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 [[Category: human cyclin-dependent kinase 6]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 20:08:27 2007''
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