1dm2

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(New page: 200px<br /> <applet load="1dm2" size="450" color="white" frame="true" align="right" spinBox="true" caption="1dm2, resolution 2.1&Aring;" /> '''HUMAN CYCLIN-DEPENDE...)
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Revision as of 14:27, 12 November 2007

Image:1dm2.gif

1dm2, resolution 2.1Å

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HUMAN CYCLIN-DEPENDENT KINASE 2 COMPLEXED WITH THE INHIBITOR HYMENIALDISINE

Overview

BACKGROUND: Over 2000 protein kinases regulate cellular functions., Screening for inhibitors of some of these kinases has already yielded some, potent and selective compounds with promising potential for the treatment, of human diseases. RESULTS: The marine sponge constituent hymenialdisine, is a potent inhibitor of cyclin-dependent kinases, glycogen synthase, kinase-3beta and casein kinase 1. Hymenialdisine competes with ATP for, binding to these kinases. A CDK2-hymenialdisine complex crystal structure, shows that three hydrogen bonds link hymenialdisine to the Glu81 and Leu83, residues of CDK2, as observed with other inhibitors. Hymenialdisine, inhibits CDK5/p35 in vivo as demonstrated by the lack of, phosphorylation/down-regulation of Pak1 kinase in E18 rat cortical, neurons, and also inhibits GSK-3 in vivo as shown by the inhibition of, MAP-1B phosphorylation. Hymenialdisine also blocks the in vivo, phosphorylation of the microtubule-binding protein tau at sites that are, hyperphosphorylated by GSK-3 and CDK5/p35 in Alzheimer's disease, (cross-reacting with Alzheimer's-specific AT100 antibodies). CONCLUSIONS:, The natural product hymenialdisine is a new kinase inhibitor with, promising potential applications for treating neurodegenerative disorders.

About this Structure

1DM2 is a Single protein structure of sequence from Homo sapiens with HMD and EDO as ligands. Full crystallographic information is available from OCA.

Reference

Inhibition of cyclin-dependent kinases, GSK-3beta and CK1 by hymenialdisine, a marine sponge constituent., Meijer L, Thunnissen AM, White AW, Garnier M, Nikolic M, Tsai LH, Walter J, Cleverley KE, Salinas PC, Wu YZ, Biernat J, Mandelkow EM, Kim SH, Pettit GR, Chem Biol. 2000 Jan;7(1):51-63. PMID:10662688

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