Mutations in a human kinase cause drug resistance by shifting conformational state distributions

Silva, Gabriel M. da; Rubenstein, Brenda M.

doi:10.1016/j.bpj.2022.11.295

Cited by 1 publication

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Section: Resultsmentioning

confidence: 99%

“…To accomplish this, we used the representative trajectories selected from the weighted ensemble simulation results described above, and analyzed the formation or breaking of electrostatic interactions involving Glu255 in these trajectories. As previously mentioned, these sample trajectories are deposited in this study’s GitHub repository [41]. The results for a subset of potentially important interactions are summarized in Figure 7.…”

Section: Resultsmentioning

confidence: 99%

“…To do so, we selected sample trajectories containing the successful flip event (DFG-in to DFG-out) along the most frequent pathway (concerted flip), and analyzed the evolution of key structural elements thought or known to be important for the DFG flip. The results of this analysis are reported in Figure 4, and the selected trajectories accompanied by their topology files are available in the project's GitHub repository [41]. 9 In the concerted pathway, the first stage of the flip corresponds to the partial flips of Asp381 and Phe382 (DFG-in to DFG-inter), and the second corresponds to the completion of the Asp381 flip in concert with the completion of the Phe382 flip (DFG-inter to DFG-out).…”

Section: Molecular Mechanism Of the Dfg Flipmentioning

confidence: 99%

“…The datasets from this study are available from the authors upon request. The code and scripts that underlie the simulations discussed in this study may be found in our manuscript GitHub Repository [41].…”

Section: Author Contributionsmentioning

confidence: 99%

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Compound Mutations in the Abl1 Kinase Cause Inhibitor Resistance by Shifting DFG Flip Mechanisms and Relative State Populations

Monteiro da Silva,

Lam,

Dalgarno

et al. 2024

Preprint

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The intrinsic dynamics of most proteins are central to their function. Protein tyrosine kinases such as Abl1 undergo significant conformational changes that modulate their activity in response to different stimuli. These conformational changes constitute a conserved mechanism for self-regulation that dramatically impacts kinases’ affinities for inhibitors. Few studies have attempted to extensively sample the pathways and elucidate the mechanisms that underlie kinase inactivation. In large part, this is a consequence of the steep energy barriers associated with many kinase conformational changes, which present a significant obstacle for computational studies using traditional simulation methods. Seeking to bridge this knowledge gap, we present a thorough analysis of the “DFG flip” inactivation pathway in Abl1 kinase. By leveraging the power of the Weighted Ensemble methodology, which accelerates sampling without the use of biasing forces, we have comprehensively simulated DFG flip events in Abl1 and its inhibitor-resistant variants, revealing a rugged landscape punctuated by potentially druggable intermediate states. Through our strategy, we successfully simulated dozens of uncorrelated DFG flip events distributed along two principal pathways, identified the molecular mechanisms that govern them, and measured their relative probabilities. Further, we show that the compound Glu255Lys/Val Thr315Ile Abl1 variants owe their inhibitor resistance phenotype to an increase in the free energy barrier associated with completing the DFG flip. This barrier stabilizes Abl1 variants in conformations that can lead to loss of binding for Type-II inhibitors such as Imatinib or Ponatinib. Finally, we contrast our Abl1 observations with the relative state distributions and propensity for undergoing a DFG flip of evolutionarily-related protein tyrosine kinases with diverging Type-II inhibitor binding affinities. Altogether, we expect that our work will be of significant importance for protein tyrosine kinase inhibitor discovery, while also furthering our understanding of how enzymes self-regulate through highly-conserved molecular switches.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Molecular Mechanism Of the Dfg Flipmentioning

confidence: 99%

Section: Author Contributionsmentioning

confidence: 99%

See 2 more Smart Citations

Compound Mutations in the Abl1 Kinase Cause Inhibitor Resistance by Shifting DFG Flip Mechanisms and Relative State Populations

Monteiro da Silva,

Lam,

Dalgarno

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

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Mutations in a human kinase cause drug resistance by shifting conformational state distributions

Cited by 1 publication

References 0 publications

Compound Mutations in the Abl1 Kinase Cause Inhibitor Resistance by Shifting DFG Flip Mechanisms and Relative State Populations

Compound Mutations in the Abl1 Kinase Cause Inhibitor Resistance by Shifting DFG Flip Mechanisms and Relative State Populations

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