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Allosteric inhibition of the epidermal growth factor receptor through disruption of transmembrane interactions

View ORCID ProfileJennifer A Rybak, Amita R Sahoo, Soyeon Kim, Robert J Pyron, Savannah B Pitts, Saffet Guleryuz, Adam W Smith, Matthias Buck, View ORCID ProfileFrancisco N Barrera
doi: https://doi.org/10.1101/2022.10.31.514582
Jennifer A Rybak
1Department of Genome Sciences and Technology, University of Tennessee, 1311 Cumberland Avenue, Knoxville, TN 37996, USA
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  • ORCID record for Jennifer A Rybak
Amita R Sahoo
2Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA
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Soyeon Kim
3Department of Chemistry, University of Akron, 190 Buchtel Common, Akron, Ohio 44325, USA
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Robert J Pyron
4Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, 1311 Cumberland Avenue, Knoxville, TN 37996, USA
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Savannah B Pitts
4Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, 1311 Cumberland Avenue, Knoxville, TN 37996, USA
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Saffet Guleryuz
5Department of Medicine, University of Tennessee Graduate School of Medicine, 1924 Alcoa Hwy, Knoxville, TN, 37920, USA
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Adam W Smith
3Department of Chemistry, University of Akron, 190 Buchtel Common, Akron, Ohio 44325, USA
6Department of Chemistry and Biochemistry, Texas Tech University, 2500 Broadway St, Lubbock, TX 79409
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Matthias Buck
2Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA
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Francisco N Barrera
4Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, 1311 Cumberland Avenue, Knoxville, TN 37996, USA
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  • For correspondence: fbarrera@utk.edu
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Abstract

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) commonly targeted for inhibition by anti-cancer therapeutics. Current therapeutics target EGFR’s kinase domain or extracellular region. However, these types of inhibitors are not specific for tumors over healthy tissue and therefore cause undesirable side effects. Our lab has recently developed a new strategy to regulate RTK activity by designing a peptide that specifically binds to the transmembrane (TM) region of the RTK to allosterically modify kinase activity. These peptides are acidity-responsive, allowing them to preferentially target acidic environments like tumors. We have applied this strategy to EGFR and created the PET1 peptide. We observed that PET1 behaves as a pH-responsive peptide that modulates the configuration of the EGFR TM through a direct interaction. Our data indicated that PET1 inhibits EGFR-mediated cell migration. Finally, we investigated the mechanism of inhibition through molecular dynamics simulations, which showed that PET1 sits between the EGFR TM dimer. We propose that the resulting disruption of native TM interactions disrupts the conformation of the kinase domain, inhibiting EGFR’s ability to send migratory cell signals. This study is a proof-of-concept that acidity-responsive membrane peptide ligands can be generally applied to RTKs. In addition, PET1 constitutes a viable approach to therapeutically target the TM of EGFR.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted November 01, 2022.
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Allosteric inhibition of the epidermal growth factor receptor through disruption of transmembrane interactions
Jennifer A Rybak, Amita R Sahoo, Soyeon Kim, Robert J Pyron, Savannah B Pitts, Saffet Guleryuz, Adam W Smith, Matthias Buck, Francisco N Barrera
bioRxiv 2022.10.31.514582; doi: https://doi.org/10.1101/2022.10.31.514582
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Allosteric inhibition of the epidermal growth factor receptor through disruption of transmembrane interactions
Jennifer A Rybak, Amita R Sahoo, Soyeon Kim, Robert J Pyron, Savannah B Pitts, Saffet Guleryuz, Adam W Smith, Matthias Buck, Francisco N Barrera
bioRxiv 2022.10.31.514582; doi: https://doi.org/10.1101/2022.10.31.514582

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