Two-state dynamics of the SH3–SH2 tandem of Abl kinase and the allosteric role of the N-cap

Corbi‐Verge, Carles; Marinelli, Fabrizio; Zafra-Ruano, Ana; Ruiz-Sanz, Javier; Luque, Irene; Faraldo‐Gómez, José D.

doi:10.1073/pnas.1303966110

Cited by 35 publications

(59 citation statements)

References 53 publications

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“…The connector SH2-KD plays a central role in Abl regulation as has been highlighted by a number of previous reports 7,26,35,36 . The S140R/I substitution in particular causes a pronounced increase in Abl activity and shows increased resistance to the KD inhibitor imatinib 7,13 .…”

Section: Resultsmentioning

confidence: 91%

“…Abl, like many other kinases, is known to function as a graded rather than simply an “on” and “off” switch 19,20 . Given the dynamic nature of protein kinases 21–23 insight into their conformational and energetic landscape 24–26 is required to fully understand the underlying mechanisms of regulation and how kinases respond to diverse signals.…”

Section: Introductionmentioning

confidence: 99%

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Atomic view of the energy landscape in the allosteric regulation of Abl kinase

Saleh

Rossi

2017

Nat Struct Mol Biol

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The activity of protein kinases is often regulated in an intramolecular fashion by signaling domains, which feature several phosphorylation or protein-docking sites. How kinases integrate such distinct binding and signaling events to regulate their activities is unclear, especially in quantitative terms. We have used NMR spectroscopy to show how structural elements within the Abl regulatory module (RM) form synergistically a multilayered allosteric mechanism that enables Abl kinase to function as a finely-tuned switch. We dissected the structure and energetics of the regulatory mechanism to precisely measure the effect of various stimuli, activating or inhibiting, on the Abl kinase activity. The data provide the mechanistic basis for explaining genetic observations and reveal a novel activator region within Abl. Our findings show that drug-resistant mutations in the Abl RM exert their allosteric effect by promoting the activated state of Abl and not by decreasing the drug affinity for the kinase.

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Section: Resultsmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Atomic view of the energy landscape in the allosteric regulation of Abl kinase

Saleh

Rossi

2017

Nat Struct Mol Biol

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“…Microsecond all-atom simulations and differential scanning calorimetry have investigated the dynamics of the SH3-SH2 tandem that operates as a two-state switch, alternating between conformations observed in the autoinhibited and active complexes 63 . The biophysical, biochemical and computational studies of Abl and Src regulation have indicated a complex interplay between the SH3 and SH2 domains, the SH2 linker and the catalytic domain.…”

Section: Introductionmentioning

confidence: 99%

“…Computational approaches have studied the atomic details of the protein kinase dynamics and regulation at different levels of complexity : from detailed analyses of the catalytic domain and drug resistance [51][52][53][54][55][56][57][58][59] to simulations of the regulatory assemblies [60][61][62][63][64] . In our previous studies, we analyzed mechanisms of allosteric kinase regulation by integrating multiscale simulations and modeling of long-range communications 60,61 .…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulations and Structural Network Analysis of c-Abl and c-Src Kinase Core Proteins: Capturing Allosteric Mechanisms and Communication Pathways from Residue Centrality

Tse

Verkhivker

2015

J. Chem. Inf. Model.

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The Abl and Src tyrosine kinases play a fundamental regulatory role in orchestrating functional processes in cellular networks and represent an important class of therapeutic targets. Crystallographic studies of these kinases have revealed a similar structural organization of multidomain complexes that confers salient features of their regulatory mechanisms. Molecular characterization of the interaction networks and regulatory residues by which the SH3 and SH2 domains act cooperatively with the catalytic domain to suppress or promote kinase activation presents an active area of structural, biochemical, and computational investigations. In this work, we combine biophysical simulations with computational modeling of the residue interaction networks to characterize allosteric mechanisms of kinase regulation and gain insight into differential sensitivity of c-Abl and c-Src kinases to specific drug binding. Using these approaches, we examine dynamics of cooperative rearrangements in the residue interaction networks and elucidate the structural role of regulatory residues responsible for modulation of kinase activity. We have found that global network parameters such as residue centrality can unambiguously distinguish functional sites that are responsible for mediating allosteric interactions in the regulatory assemblies. This study has revealed mechanistic aspects of allosteric mechanisms and communication pathways by which the SH3 and SH2 domains may exert their regulatory influence on the catalytic domain and kinase activity. We have also found that high centrality residues can be linked to each other to form efficient and robust routes that transmit allosteric signals between spatially separated regulatory regions. The presented results have demonstrated that global features of the residue interaction networks may serve as transparent and robust indicators of kinase regulatory mechanisms and accurately pinpoint key functional residues.

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“…Many longer simulations focus on the alteration of key structural features (e.g., salt bridges, domain or feature orientation and drug binding) and how these affect the free energy landscape of the protein [62][63][64][65]. These types of studies have provided information on the progression of these proteins into more active conformations following disease causing mutations [64,66] as well as critical information on the effect of mutations on drug resistance [65,66].…”

Section: From Numbers To Predictions: In Silico Analysis Of Mutationsmentioning

confidence: 99%

Using Large-Scale Genomics Data to Identify Driver Mutations in Lung Cancer: Methods and Challenges

et al. 2015

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Lung cancer is the commonest cause of cancer death in the world and carries a poor prognosis for most patients. While precision targeting of mutated proteins has given some successes for never- and light-smoking patients, there are no proven targeted therapies for the majority of smokers with the disease. Despite sequencing hundreds of lung cancers, known driver mutations are lacking for a majority of tumors. Distinguishing driver mutations from inconsequential passenger mutations in a given lung tumor is extremely challenging due to the high mutational burden of smoking-related cancers. Here we discuss the methods employed to identify driver mutations from these large datasets. We examine different approaches based on bioinformatics, in silico structural modeling and biological dependency screens and discuss the limitations of these approaches.

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Two-state dynamics of the SH3–SH2 tandem of Abl kinase and the allosteric role of the N-cap

Cited by 35 publications

References 53 publications

Atomic view of the energy landscape in the allosteric regulation of Abl kinase

Atomic view of the energy landscape in the allosteric regulation of Abl kinase

Molecular Dynamics Simulations and Structural Network Analysis of c-Abl and c-Src Kinase Core Proteins: Capturing Allosteric Mechanisms and Communication Pathways from Residue Centrality

Using Large-Scale Genomics Data to Identify Driver Mutations in Lung Cancer: Methods and Challenges

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