Kinase conformations: A computational study of the effect of ligand binding

Helms, Volkhard; McCammon, J. Andrew

doi:10.1002/pro.5560061106

Cited by 17 publications

(6 citation statements)

References 53 publications

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“…Due to the limited time scale of the simulations, we cannot completely exclude the possibility that the spacer deletion mutant might be more stable in a different conformation. The role of ATP in stabilizing the closed form of SRPK1 is in accord with previous experimental as well as simulation studies of cAMP-dependent protein kinase (PKA) (Cox et al, 1994;Helms and McCammon, 1997).…”

Section: Molecular Dynamics Studies Reveal Compensatory Interactions That Stabilize the Predicted Destabilization Mutationssupporting

confidence: 85%

SR Protein Kinase 1 Is Resilient to Inactivation

et al. 2007

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SR protein kinase 1 (SRPK1) is a constitutively active kinase, which processively phosphorylates multiple serines within its substrates, ASF/SF2. We describe crystallographic, molecular dynamics, and biochemical results that shed light on how SRPK1 preserves its constitutive active conformation. Our structure reveals that unlike other known active kinase structures, the activation loop remains in an active state without any specific intraprotein interactions. Moreover, SRPK1 remains active despite extensive mutation to the activation segment. Molecular dynamics simulations reveal that SRPK1 partially absorbs the effect of mutations by forming compensatory interactions that maintain a catalytically competent chemical environment. Furthermore, SRPK1 is similarly resistant to deletion of its spacer loop region. Based upon a model of SRPK1 bound to a segment encompassing the docking motif and active-site peptide of ASF/SF2, we suggest a mechanism for processive phosphorylation and propose that the atypical resiliency we observed is critical for SRPK1's processive activity.

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Section: Molecular Dynamics Studies Reveal Compensatory Interactions That Stabilize the Predicted Destabilization Mutationssupporting

confidence: 85%

SR Protein Kinase 1 Is Resilient to Inactivation

et al. 2007

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“…The catalytic core of all eukaryotic kinase enzymes is structurally conserved with bilobal structure and their catalytic activity is regulated by the flexibility of the structural motifs, the αC-helix, the activation loop, and the movement of the N-lobe relative to the C-lobe. , The critical residues identified in FDA and network analysis of MD trajectories are found to be evolutionarily conserved, and are part of these functional motifs. Community analysis of energy-based network also shows that the pairwise interaction energy pattern for residues of these motifs (αC-helix and the activation loop) is different in AMP- and ATP-bound states, which leads to rearrangement of community structure in kinase core (Figure ).…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanism of Nucleotide-Dependent Allosteric Regulation in AMP-Activated Protein Kinase

Ahalawat

Murarka

2017

J. Phys. Chem. B

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The AMP-activated protein kinase (AMPK), a central enzyme in the regulation of energy homeostasis, is an important drug target for type 2 diabetes, obesity, and cancer. Binding of adenosine nucleotides to the regulatory γ-subunit tightly regulates the activity of this enzyme. Though recent crystal structures of AMPK have provided important insights into the allosteric activation of AMPK, molecular details of the regulatory mechanism of AMPK activation is still elusive. Here, we have performed extensive all-atom molecular dynamics (MD) simulations and shown that the kinase domain (KD) and γ-subunit come closer resulting in a more compact heterotrimeric AMPK complex in AMP-bound state compared to the ATP-bound state. The binding of ATP at site 3 of regulatory γ-subunit allosterically inhibits AMPK by destabilizing different regulatory regions of α-subunit: the autoinhibitory domain, the linker region, and the activation loop of the kinase core. The catalytically important residues experience a change in mechanical stress, and major rearrangements in community structure derived from residue-residue interaction energy-based network are observed in KD and α-linker region upon binding of different nucleotides. Our results also highlight the role of conserved charged residues forming an ionic network near the site 3 of γ-subunit in allosteric communications.

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“…First of all, the interaction with the target peptides may be associated with conformational changes occurring in the kinase upon ligand binding. This includes global domain movement or local changes in the glycine rich P-loop, C-helix and activation loop 6,24 . Since the ligand-induced conformational changes in the target protein are still difficult to predict, we decided to support molecular modeling with experimental thermodynamic studies to identify the preferred sequence of the peptide part, and to check experimentally whether possible conformational changes interfere with the binding of the ATP-competitive part of a potential bi-substrate inhibitor of CK2α.…”

Section: Introductionmentioning

confidence: 99%

Rational drug-design approach supported with thermodynamic studies — a peptide leader for the efficient bi-substrate inhibitor of protein kinase CK2

Winiewska-Szajewska

Płonka

Zhukov

et al. 2019

Sci Rep

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Numerous inhibitors of protein kinases act on the basis of competition, targeting the ATP binding site. In this work, we present a procedure of rational design of a bi-substrate inhibitor, complemented with biophysical assays. The inhibitors of this type are commonly engineered by combining ligands carrying an ATP-like part with a peptide or peptide-mimicking fragment that determines specificity. Approach presented in this paper led to generation of a specific system for independent screening for efficient ligands and peptides, by means of thermodynamic measurements, that assessed the ability of the identified ligand and peptide to combine into a bi-substrate inhibitor. The catalytic subunit of human protein kinase CK2 was used as the model target. Peptide sequence was optimized using peptide libraries [KGDE]-[DE]-[ST]-[DE] 3–4 -NH 2, originated from the consensus CK2 sequence. We identified KESEEE-NH 2 peptide as the most promising one, whose binding affinity is substantially higher than that of the reference RRRDDDSDDD peptide. We assessed its potency to form an efficient bi-substrate inhibitor using tetrabromobenzotriazole (TBBt) as the model ATP-competitive inhibitor. The formation of ternary complex was monitored using Differential Scanning Fluorimetry (DSF), Microscale Thermophoresis (MST) and Isothermal Titration Calorimetry (ITC).

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Kinase conformations: A computational study of the effect of ligand binding

Cited by 17 publications

References 53 publications

SR Protein Kinase 1 Is Resilient to Inactivation

SR Protein Kinase 1 Is Resilient to Inactivation

Molecular Mechanism of Nucleotide-Dependent Allosteric Regulation in AMP-Activated Protein Kinase

Rational drug-design approach supported with thermodynamic studies — a peptide leader for the efficient bi-substrate inhibitor of protein kinase CK2

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