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 language | English |
|---|---|
| Pages (from-to) | 671-679 |
| Number of pages | 9 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 48 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Feb 10 2005 |
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ASJC Scopus subject areas
- Organic Chemistry
Cite this
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 journal › Article
}
TY - JOUR
T1 - Mechanism of CDK5/p25 binding by CDK inhibitors
AU - Mapelli, Marina
AU - Massimiliano, Lucia
AU - Crovace, Claudia
AU - Seeliger, Markus A.
AU - Tsai, Li Huei
AU - Meijer, Laurent
AU - Musacchio, Andrea
PY - 2005/2/10
Y1 - 2005/2/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=13444253813&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=13444253813&partnerID=8YFLogxK
U2 - 10.1021/jm049323m
DO - 10.1021/jm049323m
M3 - Article
C2 - 15689152
AN - SCOPUS:13444253813
VL - 48
SP - 671
EP - 679
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 3
ER -