Related Experiment Video

Updated: Sep 27, 2025

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
15:05

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation

Published on: May 20, 2020

8.8K

Q61 mutant-mediated dynamics changes of the GTP-KRAS complex probed by Gaussian accelerated molecular dynamics and

Jianzhong Chen1, Qingkai Zeng1, Wei Wang1

  • 1School of Science, Shandong Jiaotong University Jinan 250357 China chenjianzhong1970@163.com jzchen@sdjtu.edu.cn.

RSC Advances
|April 15, 2022
PubMed

Insights

Mutations in KRAS (Kirsten rat sarcoma viral oncogene homolog) at position 61 disrupt its switch domain, affecting GTP binding and potentially impacting cancer drug development.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Computational Biology

Background:

  • KRAS protein is a key regulator of cellular signaling pathways.
  • Dysregulation of KRAS is implicated in numerous cancers.
  • Understanding KRAS molecular mechanisms is crucial for targeted cancer therapies.

Purpose of the Study:

  • To investigate the molecular impact of Q61 mutations (Q61A, Q61H, Q61L) on KRAS activity.
  • To elucidate the effects of these mutations on GTP binding and effector interactions.
  • To provide insights for developing novel KRAS-targeted anti-cancer drugs.

Main Methods:

  • Multiple replica Gaussian accelerated molecular dynamics (MR-GaMD) simulations were employed.
  • Analysis of simulation trajectories to study protein dynamics and conformational changes.
  • Free energy landscape (FEL) calculations and interaction network analysis were performed.

Main Results:

  • Q61A, Q61H, and Q61L mutations significantly alter the dynamics of the KRAS switch domain.
  • These mutations induce structural disorder in the switch domain, impairing KRAS activity.
  • Disruption of hydrogen bonding interactions with GTP is identified as a key mechanism.

Conclusions:

  • The Q61 mutations destabilize KRAS-GTP binding by affecting crucial hydrogen bonds.
  • Increased disorder in the switch domain impacts KRAS effector binding.
  • Findings offer valuable information for KRAS-targeted anti-cancer drug discovery and development.

More Related Videos

Exploring Caspase Mutations and Post-Translational Modification by Molecular Modeling Approaches05:56

Exploring Caspase Mutations and Post-Translational Modification by Molecular Modeling Approaches

Published on: October 13, 2022

1.4K
Spatio-Temporal Manipulation of Small GTPase Activity at Subcellular Level and on Timescale of Seconds in Living Cells10:27

Spatio-Temporal Manipulation of Small GTPase Activity at Subcellular Level and on Timescale of Seconds in Living Cells

Published on: March 9, 2012

10.9K

Related Concept Videos

Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
4.3K
GTPases and their Regulation02:14

GTPases and their Regulation

Guanine nucleotide-binding proteins (G-proteins), also known as GTPases, are a superfamily of proteins that regulate many cellular processes, such as cell signaling, vesicular transport, and the regulation of cell shape and motility. Mutation or dysfunction of these proteins can lead to disease. There are around 40,000 known G-proteins that can broadly be classified into two groups ‒  small G-proteins consisting of a single domain and large multi-domain G-proteins.
Large G-proteins,...
8.7K
The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...
6.5K
Protein Dynamics in Living Cells01:19

Protein Dynamics in Living Cells

Different fluorescence-based techniques are used to study the protein dynamics in living cells. These techniques include FRAP, FRET, and PET.
Fluorescent recovery after photobleaching (FRAP) is a fluorescent-protein-based detection technique used to quantify protein movement rates within the cell. This method exposes a small portion of the cell to an intense laser beam. The laser beam causes permanent photobleaching of the fluorophore-tagged proteins in the exposed region. As the bleached...
2.3K
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
6.3K
Activation and Inactivation of G Proteins01:22

Activation and Inactivation of G Proteins

Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
7.8K