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Publication Citation: Study of interaction of the cyclin-dependent kinase 5 with its activator, p25 and with the p25-derived inhibitor, CIP

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Author(s): Antonio Cardone; Ram D. Sriram; Wayne Albers; Harish C. Pant;
Title: Study of interaction of the cyclin-dependent kinase 5 with its activator, p25 and with the p25-derived inhibitor, CIP
Published: January 15, 2009
Abstract: A high-affinity inhibitor protein called CIP, which can be produced by small truncations of p35, was earlier identified by Amin, Albers, and Pant. P35 is one of the physiological activators of cdk5, a member of the cyclin-dependent kinase family. These proteins are known to be associated with the hyperphosphorylation of specific neuronal proteins. This typically occurs in the case of neurodegenerative diseases such as Alzheimer s. In this paper we study in silico the binding mechanism of cdk5-p25 and cdk5-CIP complexes more in detail. This provides a better understanding of the inhibitory activity of the protein CIP. We use a geometry-based technique to verify the following hypothesis: p25 s truncation provides increased flexibility to CIP, and hence CIP is able to conform better to cdk5 interface than p25 is. Therefore CIP is expected to bind to cdk5 more easily than p25 and prevent it from reaching its active conformation. Our in silico study is based on a geometry-based alignment algorithm. The algorithm is capable of efficiently aligning two protein conformations with respect to their interfaces, which are represented as point sets. The algorithm is based on biochemical criteria as well as geometrical ones. Our results indicate the validity of the flexibility hypothesis. They could be used, along with some observations we made on cdk5 activation, as basis for a set of very targeted and therefore more efficient molecular dynamics simulations.
Citation: NIST Interagency/Internal Report (NISTIR) - 7552
Keywords: Cyclin-dependent kinase; neurodegenerative diseases; protein phosphorylation; computational geometry; feature-based shape similarity assessment; shape signature; point alignment algorithm.
Research Areas: Modeling, Drugs/Pharmaceuticals
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