Mechanism of CDK5/p25 binding by CDK inhibitors

Marina Mapelli, Lucia Massimiliano, Claudia Crovace, Markus A. Seeliger, Li Huei Tsai, Laurent Meijer, Andrea Musacchio

Research output: Contribution to journalArticle

Abstract

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 Å, 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.

Original languageEnglish
Pages (from-to)671-679
Number of pages9
JournalJournal of Medicinal Chemistry
Volume48
Issue number3
DOIs
Publication statusPublished - Feb 10 2005

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Cyclin-Dependent Kinases
Glycine
Crystals
Type C Niemann-Pick Disease
Neurodegenerative diseases
Phosphorylation
Stereoisomerism
Deregulation
Protein-Serine-Threonine Kinases
Amyotrophic Lateral Sclerosis
Neurodegenerative Diseases
Conformations
Cell Cycle
Ischemia
Cells
Pharmacology
roscovitine
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Mapelli, M., Massimiliano, L., Crovace, C., Seeliger, M. A., Tsai, L. H., Meijer, L., & Musacchio, A. (2005). Mechanism of CDK5/p25 binding by CDK inhibitors. Journal of Medicinal Chemistry, 48(3), 671-679. https://doi.org/10.1021/jm049323m

Mechanism of CDK5/p25 binding by CDK inhibitors. / Mapelli, Marina; Massimiliano, Lucia; Crovace, Claudia; Seeliger, Markus A.; Tsai, Li Huei; Meijer, Laurent; Musacchio, Andrea.

In: Journal of Medicinal Chemistry, Vol. 48, No. 3, 10.02.2005, p. 671-679.

Research output: Contribution to journalArticle

Mapelli, M, Massimiliano, L, Crovace, C, Seeliger, MA, Tsai, LH, Meijer, L & Musacchio, A 2005, 'Mechanism of CDK5/p25 binding by CDK inhibitors', Journal of Medicinal Chemistry, vol. 48, no. 3, pp. 671-679. https://doi.org/10.1021/jm049323m
Mapelli, Marina ; Massimiliano, Lucia ; Crovace, Claudia ; Seeliger, Markus A. ; Tsai, Li Huei ; Meijer, Laurent ; Musacchio, Andrea. / Mechanism of CDK5/p25 binding by CDK inhibitors. In: Journal of Medicinal Chemistry. 2005 ; Vol. 48, No. 3. pp. 671-679.
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