The Plasma Membrane as a Competitive Inhibitor and Positive Allosteric Modulator of KRas4B Signaling
Abstract
Mutant Ras proteins are important drivers of human cancers, yet no approved drugs act directly on this difficult target. Over the last decade, the idea has emerged that oncogenic signaling can be diminished by molecules that drive Ras into orientations in which effector-binding interfaces are occluded by the cell membrane. To support this approach to drug discovery, we characterize the orientational preferences of membrane-bound K-Ras4B in 1.45-ms aggregate time of atomistic molecular dynamics simulations. Herein, individual simulations probe active or inactive states of Ras on membranes with or without anionic lipids. We find that the membrane orientation of Ras is relatively insensitive to its bound guanine nucleotide and activation state but depends strongly on interactions with anionic phosphatidylserine lipids. These lipids slow Ras’ translational and orientational diffusion and promote a discrete population in which small changes in orientation control Ras’ competence to bind multiple regulator and effector proteins. Our results suggest that compound-directed conversion of constitutively active mutant Ras into functionally inactive forms may be accessible via subtle perturbations of Ras’ orientational preferences at the membrane surface.
- Authors:
- Publication Date:
- Research Org.:
- Los Alamos National Laboratory (LANL), Los Alamos, NM (United States); Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States); Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
- Sponsoring Org.:
- USDOE National Nuclear Security Administration (NNSA); National Institutes of Health (NIH); USDOE Laboratory Directed Research and Development (LDRD) Program
- OSTI Identifier:
- 1770463
- Alternate Identifier(s):
- OSTI ID: 1595656; OSTI ID: 1603824
- Report Number(s):
- LA-UR-19-30243
Journal ID: ISSN 0006-3495; S0006349520300369; PII: S0006349520300369
- Grant/Contract Number:
- 89233218CNA000001; AC52-07NA2734; AC5206NA25396; AC05-00OR22725; AC52-07NA27344; AC52-06NA25396
- Resource Type:
- Published Article
- Journal Name:
- Biophysical Journal
- Additional Journal Information:
- Journal Name: Biophysical Journal Journal Volume: 118 Journal Issue: 5; Journal ID: ISSN 0006-3495
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Neale, Chris, and García, Angel E. The Plasma Membrane as a Competitive Inhibitor and Positive Allosteric Modulator of KRas4B Signaling. United States: N. p., 2020.
Web. doi:10.1016/j.bpj.2019.12.039.
Neale, Chris, & García, Angel E. The Plasma Membrane as a Competitive Inhibitor and Positive Allosteric Modulator of KRas4B Signaling. United States. https://doi.org/10.1016/j.bpj.2019.12.039
Neale, Chris, and García, Angel E. Sun .
"The Plasma Membrane as a Competitive Inhibitor and Positive Allosteric Modulator of KRas4B Signaling". United States. https://doi.org/10.1016/j.bpj.2019.12.039.
@article{osti_1770463,
title = {The Plasma Membrane as a Competitive Inhibitor and Positive Allosteric Modulator of KRas4B Signaling},
author = {Neale, Chris and García, Angel E.},
abstractNote = {Mutant Ras proteins are important drivers of human cancers, yet no approved drugs act directly on this difficult target. Over the last decade, the idea has emerged that oncogenic signaling can be diminished by molecules that drive Ras into orientations in which effector-binding interfaces are occluded by the cell membrane. To support this approach to drug discovery, we characterize the orientational preferences of membrane-bound K-Ras4B in 1.45-ms aggregate time of atomistic molecular dynamics simulations. Herein, individual simulations probe active or inactive states of Ras on membranes with or without anionic lipids. We find that the membrane orientation of Ras is relatively insensitive to its bound guanine nucleotide and activation state but depends strongly on interactions with anionic phosphatidylserine lipids. These lipids slow Ras’ translational and orientational diffusion and promote a discrete population in which small changes in orientation control Ras’ competence to bind multiple regulator and effector proteins. Our results suggest that compound-directed conversion of constitutively active mutant Ras into functionally inactive forms may be accessible via subtle perturbations of Ras’ orientational preferences at the membrane surface.},
doi = {10.1016/j.bpj.2019.12.039},
journal = {Biophysical Journal},
number = 5,
volume = 118,
place = {United States},
year = {Sun Mar 01 00:00:00 EST 2020},
month = {Sun Mar 01 00:00:00 EST 2020}
}
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