Molecular mechanisms of activation in CDK2

Bešker, Neva; Amadei, Andrea; D’Abramo, Marco

doi:10.1080/07391102.2013.844080

Cited by 13 publications

(13 citation statements)

References 39 publications

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“…Molecular dynamics (MD) simulations and coarse-grained elastic models [ 78 , 79 ] have investigated collective motions in different CDK2 structures [ 80 – 82 ]. Simulations of conformational transitions between the open and closed states of CDK2 showed that activation may be regulated by the αC-helix and T-loop regions, which undergo large structural changes during remodeling of the kinase domain [ 83 ]. MD simulations of the CDK2-Cyclin A/substrate complex analyzed the role of the phosphorylated T160 site on dynamics and substrate binding, confirming its important role for substrate recognition and thermal stability [ 84 ].…”

Section: Introductionmentioning

confidence: 99%

Ensemble-based modeling and rigidity decomposition of allosteric interaction networks and communication pathways in cyclin-dependent kinases: Differentiating kinase clients of the Hsp90-Cdc37 chaperone

2017

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The overarching goal of delineating molecular principles underlying differentiation of protein kinase clients and chaperone-based modulation of kinase activity is fundamental to understanding activity of many oncogenic kinases that require chaperoning of Hsp70 and Hsp90 systems to attain a functionally competent active form. Despite structural similarities and common activation mechanisms shared by cyclin-dependent kinase (CDK) proteins, members of this family can exhibit vastly different chaperone preferences. The molecular determinants underlying chaperone dependencies of protein kinases are not fully understood as structurally similar kinases may often elicit distinct regulatory responses to the chaperone. The regulatory divergences observed for members of CDK family are of particular interest as functional diversification among these kinases may be related to variations in chaperone dependencies and can be exploited in drug discovery of personalized therapeutic agents. In this work, we report the results of a computational investigation of several members of CDK family (CDK5, CDK6, CDK9) that represented a broad repertoire of chaperone dependencies—from nonclient CDK5, to weak client CDK6, and strong client CDK9. By using molecular simulations of multiple crystal structures we characterized conformational ensembles and collective dynamics of CDK proteins. We found that the elevated dynamics of CDK9 can trigger imbalances in cooperative collective motions and reduce stability of the active fold, thus creating a cascade of favorable conditions for chaperone intervention. The ensemble-based modeling of residue interaction networks and community analysis determined how differences in modularity of allosteric networks and topography of communication pathways can be linked with the client status of CDK proteins. This analysis unveiled depleted modularity of the allosteric network in CDK9 that alters distribution of communication pathways and leads to impaired signaling in the client kinase. According to our results, these network features may uniquely define chaperone dependencies of CDK clients. The perturbation response scanning and rigidity decomposition approaches identified regulatory hotspots that mediate differences in stability and cooperativity of allosteric interaction networks in the CDK structures. By combining these synergistic approaches, our study revealed dynamic and network signatures that can differentiate kinase clients and rationalize subtle divergences in the activation mechanisms of CDK family members. The therapeutic implications of these results are illustrated by identifying structural hotspots of pathogenic mutations that preferentially target regions of the increased flexibility to enable modulation of activation changes. Our study offers a network-based perspective on dynamic kinase mechanisms and drug design by unravelling relationships between protein kinase dynamics, allosteric communications and chaperone dependencies.

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Section: Introductionmentioning

confidence: 99%

Ensemble-based modeling and rigidity decomposition of allosteric interaction networks and communication pathways in cyclin-dependent kinases: Differentiating kinase clients of the Hsp90-Cdc37 chaperone

2017

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“…To compare the conformational behavior of different simulations on the essential subspace, we calculated the eigenvectors from a unique trajectory as obtained by concatenating the corresponding trajectories of each system of interest. Such a procedure, successfully used in our recent paper, allows to easily compare the principal motion directions of all the system on a common essential subspace. This procedure was applied to both the C‐alpha atoms of the common longest stretch of the proteins and to the (30) C‐alpha of the residues within 10 Å of the active site, in order to compare local essential motions …”

Section: Methodsmentioning

confidence: 99%

Effect of DNA on the conformational dynamics of the endonucleases I‐DmoI as provided by molecular dynamics simulations

Grottesi¹,

Cecconi

Molina

et al. 2016

Biopolymers

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The conformational behavior of the wild-type endonucleases I-DmoI and two of its mutants has been studied in the presence and in the absence of DNA target sequences by means of extended molecular dynamics simulations. Our results show that in the absence of DNA, the three protein forms explore a similar essential conformational space, whereas when bound to the same DNA target sequence of 25 base pairs, they diversify and restrain the subspace explored. In addition, the differences in the essential subspaces explored by the residues near the catalytic site for both the bound and unbound forms are discussed in background of the experimental protein activity.

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“…Principal component analysis (PCA) [39] was performed in order to extract the more relevant motions from the trajectory. In particular, the diagonalization of the covariance matrix of the C-α fluctuations, provides a set of eigenvectors that are ordered according to the corresponding eigenvalues.…”

Section: Principal Component Analysis (Pca) and Essential Dynamics Sampling (Eds)mentioning

confidence: 99%

Modelling the Activation Pathways in Full-Length Src Kinase

2021

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Src kinases play fundamental roles in several crucial cell processes. Their activity is tightly regulated by conformational transitions between the active and the inactive forms, which are carried out by complex protein structural rearrangements. Here, we present an in-depth study of such structural transitions coupling extensive all-atoms molecular dynamic simulations coupled to an algorithm able to drive the system between defined conformational states. Our results, in line with the available experimental data, confirm the complexity of such a process indicating the main molecular determinants involved. Moreover, the role of an Src inhibitor—able to bind to the protein inactive state—is discussed and compared with available experimental data.

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Molecular mechanisms of activation in CDK2

Cited by 13 publications

References 39 publications

Ensemble-based modeling and rigidity decomposition of allosteric interaction networks and communication pathways in cyclin-dependent kinases: Differentiating kinase clients of the Hsp90-Cdc37 chaperone

Ensemble-based modeling and rigidity decomposition of allosteric interaction networks and communication pathways in cyclin-dependent kinases: Differentiating kinase clients of the Hsp90-Cdc37 chaperone

Effect of DNA on the conformational dynamics of the endonucleases I‐DmoI as provided by molecular dynamics simulations

Modelling the Activation Pathways in Full-Length Src Kinase

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