1e9h: Difference between revisions
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[[Image:1e9h.gif|left|200px]]<br /> | [[Image:1e9h.gif|left|200px]]<br /><applet load="1e9h" size="450" color="white" frame="true" align="right" spinBox="true" | ||
<applet load="1e9h" size="450" color="white" frame="true" align="right" spinBox="true" | |||
caption="1e9h, resolution 2.5Å" /> | caption="1e9h, resolution 2.5Å" /> | ||
'''THR 160 PHOSPHORYLATED CDK2-HUMAN CYCLIN A3 COMPLEX WITH THE INHIBITOR INDIRUBIN-5-SULPHONATE BOUND'''<br /> | '''THR 160 PHOSPHORYLATED CDK2-HUMAN CYCLIN A3 COMPLEX WITH THE INHIBITOR INDIRUBIN-5-SULPHONATE BOUND'''<br /> | ||
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==About this Structure== | ==About this Structure== | ||
1E9H is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with INR as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Transferred_entry:_2.7.11.1 Transferred entry: 2.7.11.1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.37 2.7.1.37] | 1E9H is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with INR as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Transferred_entry:_2.7.11.1 Transferred entry: 2.7.11.1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.37 2.7.1.37] Known structural/functional Site: <scene name='pdbsite=INA:Inr Binding Site For Chain C'>INA</scene>. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1E9H OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: phosphorylation]] | [[Category: phosphorylation]] | ||
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Revision as of 15:56, 18 December 2007
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THR 160 PHOSPHORYLATED CDK2-HUMAN CYCLIN A3 COMPLEX WITH THE INHIBITOR INDIRUBIN-5-SULPHONATE BOUND
OverviewOverview
BACKGROUND: Cyclin-dependent kinase 2 (CDK2) is an important target for, structure-based design of antitumor agents. Monomeric CDK2 is inactive., Activation requires rearrangements to key structural elements of the, enzyme's active site, which accompany cyclin binding and phosphorylation., To assess the validity of using monomeric CDK2 as a model for the active, kinase in structure-based drug design, we have solved the structure of the, inhibitor indirubin-5-sulphonate (E226) complexed with phospho-CDK2-cyclin, A and compared it with the structure of E226 bound to inactive, monomeric, CDK2. RESULTS: Activation of monomeric CDK2 leads to a rotation of its, N-terminal domain relative to the C-terminal lobe. The accompanying change, in position of E226 follows that of the N-terminal domain, and its, interactions with residues forming part of the adenine binding pocket are, conserved. The environment of the ATP-ribose site, not explored by E226, is significantly different in the binary complex compared to the monomeric, complex due to movement of the glycine loop. Conformational changes also, result in subtle differences in hydrogen bonding and electrostatic, interactions between E226's sulphonate and CDK2's phosphate binding site., Affinities calculated by LUDI for the interaction of E226 with active or, inactive CDK2 differ by a factor of approximately ten. CONCLUSIONS: The, accuracy of monomeric CDK2 as an inhibitor design template is restricted, to the adenine binding site. The general flexibility observed for the, glycine loop and subtle changes to the phosphate binding site suggest a, need to study interactions between inhibitors and active CDK2 in, structure-based drug design programs.
About this StructureAbout this Structure
1E9H is a Protein complex structure of sequences from Homo sapiens with INR as ligand. Active as Transferred entry: 2.7.11.1, with EC number 2.7.1.37 Known structural/functional Site: . Full crystallographic information is available from OCA.
ReferenceReference
Inhibitor binding to active and inactive CDK2: the crystal structure of CDK2-cyclin A/indirubin-5-sulphonate., Davies TG, Tunnah P, Meijer L, Marko D, Eisenbrand G, Endicott JA, Noble ME, Structure. 2001 May 9;9(5):389-97. PMID:11377199
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