Yazar "Jalalypour, Farzaneh" seçeneğine göre listele

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    Inhibition of mutant RAS-RAF interaction by mimicking structural and dynamic properties of phosphorylated RAS
    (NLM (Medline), 2022) İlter, Metehan; Kaşmer, Ramazan; Jalalypour, Farzaneh; Atılgan, Canan; Topçu, Ozan; Karakaş, Nihal; Şensoy, Özge
    Undruggability of RAS proteins has necessitated alternative strategies for the development of effective inhibitors. In this respect, phosphorylation has recently come into prominence as this reversible post-translational modification attenuates sensitivity of RAS towards RAF. As such, in this study, we set out to unveil the impact of phosphorylation on dynamics of HRASWT and aim to invoke similar behavior in HRASG12D mutant by means of small therapeutic molecules. To this end, we performed molecular dynamics (MD) simulations using phosphorylated HRAS and showed that phosphorylation of Y32 distorted Switch I, hence the RAS/RAF interface. Consequently, we targeted Switch I in HRASG12D by means of approved therapeutic molecules and showed that the ligands enabled detachment of Switch I from the nucleotide-binding pocket. Moreover, we demonstrated that displacement of Switch I from the nucleotide-binding pocket was energetically more favorable in the presence of the ligand. Importantly, we verified computational findings in vitro where HRASG12D/RAF interaction was prevented by the ligand in HEK293T cells that expressed HRASG12D mutant protein. Therefore, these findings suggest that targeting Switch I, hence making Y32 accessible might open up new avenues in future drug discovery strategies that target mutant RAS proteins.
  • Küçük Resim
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    Perturb-Scan-Pull: A novel method facilitating conformational transitions in proteins
    (American Chemical Society, 2020) Jalalypour, Farzaneh; Şensoy, Özge; Atılgan, Canan
    Conformational transitions in proteins facilitate precise physiological functions. Therefor; it is crucial to understand the mechanisms underlying these processes to modulate protein function. Yet, studying structural and dynamical properties of proteins is notoriously challenging due to the complexity of the underlying potential energy surfaces (PES). We have previously developed the perturbation-response scanning (PRS) method to identify key residues that participate in the communication network responsible for specific conformational transitions. PRS is based on a residue-by-residue scan of the protein to determine the subset of residues/forces which provide the closest conformational change leading to a target conformational state, inasmuch as linear response theory applies to these motions. Here, we develop a novel method to further evaluate if conformational transitions may be triggered on the PES. We aim to study functionally relevant conformational transitions in proteins by using results obtained from PRS and feeding them as inputs to steered molecular dynamics simulations. The success and the transferability of the method are evaluated on three protein systems having different complexities of motion on the PES: calmodulin, adenylate kinase, and bacterial ferric binding protein. We find that the method captures the target conformation, while providing key residues and the optimum paths with relatively low free energy profiles.