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Title: The Structural Basis for Activation and Inhibition of ZAP-70 Kinase Domain
Authors: Huber R.G.
Fan H. 
Bond P.J. 
Keywords: separase
protein binding
protein kinase ZAP 70
amino terminal sequence
carboxy terminal sequence
consensus sequence
controlled study
enzyme specificity
enzyme structure
enzyme substrate complex
mathematical model
protein domain
protein secondary structure
sequence alignment
sequence analysis
sequence homology
structural bioinformatics
binding site
chemical model
enzyme activation
enzyme stability
molecular dynamics
protein conformation
protein tertiary structure
structure activity relation
Binding Sites
Enzyme Activation
Enzyme Stability
Models, Chemical
Molecular Dynamics Simulation
Protein Binding
Protein Conformation
Protein Structure, Tertiary
Structure-Activity Relationship
Substrate Specificity
ZAP-70 Protein-Tyrosine Kinase
Issue Date: 2015
Citation: Huber R.G., Fan H., Bond P.J. (2015). The Structural Basis for Activation and Inhibition of ZAP-70 Kinase Domain. PLoS Computational Biology 11 (10) : e1004560. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: ZAP?70 (Zeta-chain-associated protein kinase 70) is a tyrosine kinase that interacts directly with the activated T-cell receptor to transduce downstream signals, and is hence a major player in the regulation of the adaptive immune response. Dysfunction of ZAP?70 causes selective T cell deficiency that in turn results in persistent infections. ZAP?70 is activated by a variety of signals including phosphorylation of the kinase domain (KD), and binding of its regulatory tandem Src homology 2 (SH2) domains to the T cell receptor. The present study investigates molecular mechanisms of activation and inhibition of ZAP?70 via atomically detailed molecular dynamics simulation approaches. We report microsecond timescale simulations of five distinct states of the ZAP?70 KD, comprising apo, inhibited and three phosphorylated variants. Extensive analysis of local flexibility and correlated motions reveal crucial transitions between the states, thus elucidating crucial steps in the activation mechanism of the ZAP?70 KD. Furthermore, we rationalize previously observed staurosporine-bound crystal structures, suggesting that whilst the KD superficially resembles an ?active-like? conformation, the inhibitor modulates the underlying protein dynamics and restricts it in a compact, rigid state inaccessible to ligands or cofactors. Finally, our analysis reveals a novel, potentially druggable pocket in close proximity to the activation loop of the kinase, and we subsequently use its structure in fragment-based virtual screening to develop a pharmacophore model. The pocket is distinct from classical type I or type II kinase pockets, and its discovery offers promise in future design of specific kinase inhibitors, whilst mutations in residues associated with this pocket are implicated in immunodeficiency in humans. ? 2015 Huber et al.
Source Title: PLoS Computational Biology
ISSN: 1553734X
DOI: 10.1371/journal.pcbi.1004560
Rights: Attribution 4.0 International
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