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- W2585087467 abstract "The deregulation of protein kinases is often related with the development of several malignancies such as cancer. Therefore, inhibition of protein kinases is an established and often effective pharmacological strategy. However, point mutations in kinases are frequently the cause of drug resistance. To overcome this issue, many efforts are directed towards the design of allosteric drugs, with the goal to inhibit the mutated forms of kinases. To understand the molecular basis of the allosteric control of protein kinases is essential for the design of novel drugs. In this work, we focus on the prototype Abl kinase. Experimental studies have demonstrated that the binding of the SH2 domain on the kinase domain enhances the A-loop trans-autophosphorylation, a required step for full kinase activity. Hence, the SH2 domain acts as an allosteric modulator. However, it is yet poorly understood how the SH2 domain affects the A-loop accessibility. Here, we coupled MD simulations with free energy calculations to investigate possible mechanisms for such allosteric control in Abl. We found that the A-loop plasticity is affected by a complex network of interactions that involve several Abl structural features, such as the DFG motif, the HRD motif and the SH2 domain. Hence, we hypothesize that such elements might constitute additional layers that control the Abl allosteric machinery. These results provide important hints for deciphering the complex signaling network for Abl activation. Moreover, these findings may help the rational design of Abl binders capable of interfering with such activation mechanism. Finally, since the SH2 domain is found in several other protein kinases, we propose that such a mechanism may be extended to several kinases which are currently under investigations in our labs." @default.
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- W2585087467 date "2017-02-01" @default.
- W2585087467 modified "2023-10-01" @default.
- W2585087467 title "Molecular Simulations to Unravel the Allosteric Interplay between the SH2 Domain and A-loop Plasticity in Protein Kinases" @default.
- W2585087467 doi "https://doi.org/10.1016/j.bpj.2016.11.206" @default.
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