1995 Fiscal Year Final Research Report Summary
Analysis of the substrate specificities of cyclin-dependent protein kinases and application to development of specific inhibitors
| Project/Area Number |
06680569
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Bioorganic chemistry
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| Research Institution | Saga Medical School (1995)
Aichi Cancer Center Research Institute (1994) |
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Principal Investigator |
ANDO Shoji Saga Medical School, Chemistry Laboratory, Associate Professor, 医学部, 助教授 (20193104)
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| Project Period (FY) |
1994 – 1995
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| Keywords | Cyclin-dependent protein kinase / Protein phosphorylation / Substrate specificity / Enzyme inhibitor |
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| Research Abstract |
Cdc2 kinase or cdk5, a member ofcyclin-dependent protein kinases, phosphorylates a Ser/Thr site immediately followed by a proline which acts as the substrate specificity determinant for the kinases. We found that a proline in a peptide substrate for cdc2 kinase can be replaced partly by sarcosine, suggesting that the N-substituted structure of proline is an important factor for the substrate recognition by the kinase. To gain a better understanding the proline-directed phosphorylation, the proline residue in the peptide representing the site in vimentin for cdc2 kinase was replaced by various N-methylamino acids or proline homologs. The results obtained here suggested that the ring structure, especially the pyrrolidine ring structure of proline is important for the substrate recognition and phosphorylation by cdc2 kinase. Moreover, molecular modeling, together with the biochemical results, suggested that the extent of phosphorylation is related to how well each peptide can assume a turn structure around the site. Proline might be required to form and stabilize a turn structure, which might be preferable to be recognized by cdc2 kinase. Cdk5 also showed a similar but relatively strict proline-specificity compared to that of cdc2 kinase. These results would afford useful information for developing specific inhibitors for cyclin-dependent protein kinases.
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