Inhibition of mutant RAS-RAF interaction by mimicking structural and dynamic properties of phosphorylated RAS

  1. Metehan Ilter
  2. Ramazan Kaşmer
  3. Farzaneh Jalalypour
  4. Canan Atilgan
  5. Ozan Topcu
  6. Nihal Karakaş  Is a corresponding author
  7. Ozge Sensoy  Is a corresponding author
  1. Istanbul Medipol University, Turkey
  2. Sabanci University, Turkey

Abstract

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.

Data availability

Simulated data used to generate the figures in the commentary are available online (https://osf.io/z2y5s/?view_only=070ebb995ba945bb9aac40d5979bd508).

Article and author information

Author details

  1. Metehan Ilter

    1Graduate School of Engineering and Natural Sciences, Istanbul Medipol University, Istanbul, Turkey
    Competing interests
    The authors declare that no competing interests exist.
  2. Ramazan Kaşmer

    Institute for Health Sciences and Technologies, Istanbul Medipol University, Istanbul, Turkey
    Competing interests
    The authors declare that no competing interests exist.
  3. Farzaneh Jalalypour

    Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey
    Competing interests
    The authors declare that no competing interests exist.
  4. Canan Atilgan

    Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0557-6044
  5. Ozan Topcu

    Institute for Health Sciences and Technologies, Istanbul Medipol University, Istanbul, Turkey
    Competing interests
    The authors declare that no competing interests exist.
  6. Nihal Karakaş

    Institute for Health Sciences and Technologies, Istanbul Medipol University, Istanbul, Turkey
    For correspondence
    nkarakas@medipol.edu.tr
    Competing interests
    The authors declare that no competing interests exist.
  7. Ozge Sensoy

    Institute for Health Sciences and Technologies, Istanbul Medipol University, Istanbul, Turkey
    For correspondence
    osensoy@medipol.edu.tr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5950-3436

Funding

Health Institute of Turkey (3561/2019-TA-02)

  • Metehan Ilter
  • Ozan Topcu
  • Ozge Sensoy

The Scientific and Technological Research Council of Turkey (116F229)

  • Farzaneh Jalalypour
  • Canan Atilgan

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Qiang Cui, Boston University, United States

Version history

  1. Preprint posted: April 24, 2022 (view preprint)
  2. Received: April 25, 2022
  3. Accepted: November 30, 2022
  4. Accepted Manuscript published: December 2, 2022 (version 1)
  5. Accepted Manuscript updated: December 5, 2022 (version 2)
  6. Version of Record published: December 19, 2022 (version 3)

Copyright

© 2022, Ilter et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Metehan Ilter
  2. Ramazan Kaşmer
  3. Farzaneh Jalalypour
  4. Canan Atilgan
  5. Ozan Topcu
  6. Nihal Karakaş
  7. Ozge Sensoy
(2022)
Inhibition of mutant RAS-RAF interaction by mimicking structural and dynamic properties of phosphorylated RAS
eLife 11:e79747.
https://doi.org/10.7554/eLife.79747

Share this article

https://doi.org/10.7554/eLife.79747

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