2a4l: Difference between revisions

Revision as of 17:23, 21 February 2008

Human cyclin-dependent kinase 2 in complex with roscovitine

OverviewOverview

Cyclin-dependent kinases (cdk) control the cell division cycle (cdc). These kinases and their regulators are frequently deregulated in human tumours. A potent inhibitor of cdks, roscovitine [2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurin e], was identified by screening a series of C2,N6,N9-substituted adenines on purified cdc2/cyclin B. Roscovitine displays high efficiency and high selectivity (Meijer, L., Borgne, A., Mulner, O., Chong, J. P. J., Blow, J. J., Inagaki, N., Inagaki, M., Delcros, J.-G. & Moulinoux, J.-P. (1997) Eur. J. Biochem. 243, 527-536). It behaves as a competitive inhibitor for ATP binding to cdc2. We determined the crystal structure of a complex between cdk2 and roscovitine at 0.24-nm (2.4 A) resolution and refined to an Rfactor of 0.18. The purine portion of the inhibitor binds to the adenine binding pocket of cdk2. The position of the benzyl ring group of the inhibitor enables the inhibitor to make contacts with the enzyme not observed in the ATP-complex structure. Analysis of the position of this benzyl ring explains the specificity of roscovitine in inhibiting cdk2. The structure also reveals that the (R)-stereoisomer of roscovitine is bound to cdk2. The (R)-isomer is about twice as potent in inhibiting cdc2/cyclin B than the (S)-isomer. Results from structure/activity studies and from analysis of the cdk2/roscovitine complex crystal structure should allow the design of even more potent cdk inhibitors.

About this StructureAbout this Structure

2A4L is a Single protein structure of sequence from Homo sapiens 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

Inhibition of cyclin-dependent kinases by purine analogues: crystal structure of human cdk2 complexed with roscovitine., De Azevedo WF, Leclerc S, Meijer L, Havlicek L, Strnad M, Kim SH, Eur J Biochem. 1997 Jan 15;243(1-2):518-26. PMID:9030780

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-[[Image:2a4l.jpg|left|200px]]<br /><applet load="2a4l" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:2a4l.jpg|left|200px]]<br /><applet load="2a4l" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="2a4l, resolution 2.4&Aring;" />
 '''Human cyclin-dependent kinase 2 in complex with roscovitine'''<br />
 ==Overview==
-Cyclin-dependent kinases (cdk) control the cell division cycle (cdc)., These kinases and their regulators are frequently deregulated in human, tumours. A potent inhibitor of cdks, roscovitine, [2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurin e], was, identified by screening a series of C2,N6,N9-substituted adenines on, purified cdc2/cyclin B. Roscovitine displays high efficiency and high, selectivity (Meijer, L., Borgne, A., Mulner, O., Chong, J. P. J., Blow, J., J., Inagaki, N., Inagaki, M., Delcros, J.-G. &amp; Moulinoux, J.-P. (1997), Eur. J. Biochem. 243, 527-536). It behaves as a competitive inhibitor for, ATP binding to cdc2. We determined the crystal structure of a complex, between cdk2 and roscovitine at 0.24-nm (2.4 A) resolution and refined to, an Rfactor of 0.18. The purine portion of the inhibitor binds to the, adenine binding pocket of cdk2. The position of the benzyl ring group of, the inhibitor enables the inhibitor to make contacts with the enzyme not, observed in the ATP-complex structure. Analysis of the position of this, benzyl ring explains the specificity of roscovitine in inhibiting cdk2., The structure also reveals that the (R)-stereoisomer of roscovitine is, bound to cdk2. The (R)-isomer is about twice as potent in inhibiting, cdc2/cyclin B than the (S)-isomer. Results from structure/activity studies, and from analysis of the cdk2/roscovitine complex crystal structure should, allow the design of even more potent cdk inhibitors.
+Cyclin-dependent kinases (cdk) control the cell division cycle (cdc). These kinases and their regulators are frequently deregulated in human tumours. A potent inhibitor of cdks, roscovitine [2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurin e], was identified by screening a series of C2,N6,N9-substituted adenines on purified cdc2/cyclin B. Roscovitine displays high efficiency and high selectivity (Meijer, L., Borgne, A., Mulner, O., Chong, J. P. J., Blow, J. J., Inagaki, N., Inagaki, M., Delcros, J.-G. &amp; Moulinoux, J.-P. (1997) Eur. J. Biochem. 243, 527-536). It behaves as a competitive inhibitor for ATP binding to cdc2. We determined the crystal structure of a complex between cdk2 and roscovitine at 0.24-nm (2.4 A) resolution and refined to an Rfactor of 0.18. The purine portion of the inhibitor binds to the adenine binding pocket of cdk2. The position of the benzyl ring group of the inhibitor enables the inhibitor to make contacts with the enzyme not observed in the ATP-complex structure. Analysis of the position of this benzyl ring explains the specificity of roscovitine in inhibiting cdk2. The structure also reveals that the (R)-stereoisomer of roscovitine is bound to cdk2. The (R)-isomer is about twice as potent in inhibiting cdc2/cyclin B than the (S)-isomer. Results from structure/activity studies and from analysis of the cdk2/roscovitine complex crystal structure should allow the design of even more potent cdk inhibitors.
 ==About this Structure==
-A4L is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with RRC 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=2A4L OCA].
+A4L is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=RRC:'>RRC</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=2A4L OCA].
 ==Reference==
@@ Line 14: / Line 14: @@
 [[Category: Non-specific serine/threonine protein kinase]]
 [[Category: Single protein]]
-[[Category: Jr., W.F.De.Azevedo.]]
+[[Category: Jr., W F.De Azevedo.]]
-[[Category: Kim, S.H.]]
+[[Category: Kim, S H.]]
 [[Category: RRC]]
 [[Category: atp-binding]]
@@ Line 25: / Line 25: @@
 [[Category: transferase]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 07:54:41 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:23:34 2008''