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==Overview== | ==Overview== | ||
The cyclin-dependent kinases (CDK) CDK1, CDK2, CDK4, and CDK6 are, serine/threonine protein kinases targeted in cancer therapy due to their, role in cell cycle progression. The postmitotic CDK5 is involved in, biological pathways important for neuronal migration and differentiation., CDK5 represents an attractive pharmacological target as its deregulation, is implicated in various neurodegenerative diseases such as Alzheimer's, Parkinson's, and Niemann-Pick type C diseases, ischemia, and amyotrophic, lateral sclerosis. We have generated an improved crystal form of CDK5 in, complex with p25, a segment of the p35 neuronal activator. The crystals, were used to solve the structure of CDK5/p25 with (R)-roscovitine and, aloisine at a resolution of 2.2 and 2.3 A, respectively. The structure of, CDK5/p25/roscovitine provides a rationale for the preference of CDK5 for, the R over the S stereoisomer. Furthermore, roscovitine stabilized an, unusual collapsed conformation of the glycine-rich loop, an important site, of CDK regulation, and we report an investigation of the effects of, glycine-rich loop phosphorylation on roscovitine binding. The CDK5/p25, crystals represent a valuable new tool for the identification and, optimization of selective CDK inhibitors. | The cyclin-dependent kinases (CDK) CDK1, CDK2, CDK4, and CDK6 are, serine/threonine protein kinases targeted in cancer therapy due to their, role in cell cycle progression. The postmitotic CDK5 is involved in, biological pathways important for neuronal migration and differentiation., CDK5 represents an attractive pharmacological target as its deregulation, is implicated in various neurodegenerative diseases such as Alzheimer's, Parkinson's, and Niemann-Pick type C diseases, ischemia, and amyotrophic, lateral sclerosis. We have generated an improved crystal form of CDK5 in, complex with p25, a segment of the p35 neuronal activator. The crystals, were used to solve the structure of CDK5/p25 with (R)-roscovitine and, aloisine at a resolution of 2.2 and 2.3 A, respectively. The structure of, CDK5/p25/roscovitine provides a rationale for the preference of CDK5 for, the R over the S stereoisomer. Furthermore, roscovitine stabilized an, unusual collapsed conformation of the glycine-rich loop, an important site, of CDK regulation, and we report an investigation of the effects of, glycine-rich loop phosphorylation on roscovitine binding. The CDK5/p25, crystals represent a valuable new tool for the identification and, optimization of selective CDK inhibitors. | ||
==Disease== | |||
Known diseases associated with this structure: Microcephaly, primary autosomal recessive, 3 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608201 608201]] | |||
==About this Structure== | ==About this Structure== | ||
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[[Category: neurodegenerative diseases]] | [[Category: neurodegenerative diseases]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 19:36:48 2007'' | ||
