Structural and Dynamic Determinants of Ligand Binding and Regulation of Cyclin-Dependent Kinase 5 by Pathological Activator p25 and Inhibitory Peptide CIP

JOURNAL OF MOLECULAR BIOLOGY

卷:401

Article

Cardone, A.^2,3  Hassan, S. A.¹  Albers, R. W.⁴  Sriram, R. D.²  Pant, H. C.⁵ 

[1] NIH, Ctr Mol Modeling, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA

[2] NIST, Informat Technol Lab, Gaithersburg, MD 20899 USA

[3] Univ Maryland, Dept Mech Engn, College Pk, MD 20742 USA

[4] Natl Inst Neurol Disorders & Stroke, Enzyme Chem Sect, Neurochem Lab, NIH, Bethesda, MD 20892 USA

[5] Natl Inst Neurol Disorders & Stroke, Neuronal Cytoskeletal Prot Regulat Sect, Neurochem Lab, NIH, Bethesda, MD 20892 USA

关键词: cdk5;    CIP;    kinase;    regulation;    dynamics;   

DOI  :  10.1016/j.jmb.2010.06.040

来源: Elsevier

【 摘 要 】

The crystal structure of the cdk5/p25 complex has provided information on possible molecular mechanisms of the ligand binding, specificity, and regulation of the kinase. Comparative molecular dynamics simulations are reported here for physiological conditions. This study provides new insight on the mechanisms that modulate such processes, which may be exploited to control pathological activation by p25. The structural changes observed in the kinase are stabilized by a network of interactions involving highly conserved residues within the cyclin-dependent kinase (cdk) family. Collective motions of the proteins (cdk5, p25, and CIP) and their complexes are identified by principal component analysis, revealing two conformational states of the activation loop upon p25 complexation, which are absent in the uncomplexed kinase and not apparent from the crystal. Simulations of the uncomplexed inhibitor CIP show structural rearrangements and increased flexibility of the interfacial loop containing the critical residue E240, which becomes fully hydrated and available for interactions with one of several positively charged residues in the kinase. These changes provide a rationale for the observed high affinity and enhanced inhibitory action of CIP when compared to either p25 or the physiological activators of cdk5. Published by Elsevier Ltd.

【 授权许可】

Free