Related Experiment Video

Updated: Aug 2, 2025

Single-Molecule FRET Imaging for Observing the Conformational Dynamics of Dynamin-Like GTPase Atlastin
10:19

Single-Molecule FRET Imaging for Observing the Conformational Dynamics of Dynamin-Like GTPase Atlastin

Published on: January 24, 2025

571

Probing mutation-induced conformational transformation of the GTP/M-RAS complex through Gaussian accelerated

Huayin Bao1, Wei Wang2, Haibo Sun2

  • 1School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China.

Journal of Enzyme Inhibition and Medicinal Chemistry
|April 14, 2023
PubMed

Insights

Mutations in M-RAS switch domains increase disorder and alter flexibility, impacting cancer drug targets. This research reveals molecular mechanisms for M-RAS function and anticancer drug design.

Area of Science:

  • Molecular biology
  • Computational chemistry
  • Structural biology

Background:

  • M-RAS is a key target in anticancer drug design due to its role in cell signaling.
  • Mutations in M-RAS can significantly alter its structural flexibility and function.
  • Understanding these alterations is crucial for developing effective cancer therapies.

Purpose of the Study:

  • To investigate the impact of specific M-RAS mutations (P40D, D41E, P40D/D41E/L51R) on the conformational dynamics of switch domains.
  • To elucidate the molecular mechanisms underlying M-RAS dysfunction caused by these mutations.
  • To provide insights for future anticancer drug design targeting M-RAS.

Main Methods:

  • Gaussian accelerated molecular dynamics (GaMD) simulations were employed to study the GTP-bound M-RAS.
  • Free energy landscapes (FELs) were analyzed to assess conformational changes.
  • Principal component analysis (PCA) and dynamics analysis were used to evaluate structural flexibility and collective motions.

Main Results:

  • The studied mutations induce less energetic and more disordered states in M-RAS switch domains compared to wild-type.
  • Mutations significantly affect the collective motions and flexibility of switch domains, overlapping with effector binding sites.
  • Instability in hydrogen bonding interactions of GTP with specific residues drives the disordered states of the switch domains.

Conclusions:

  • Mutations in M-RAS switch domains lead to increased disorder and altered flexibility, disrupting M-RAS activity.
  • The findings offer a molecular understanding of M-RAS function and its dysregulation in cancer.
  • This study provides a foundation for designing novel anticancer drugs targeting M-RAS.
Keywords:
M-RAS GTP Gaussian accelerated molecular dynamics free energy landscapes principal component analysis

More Related Videos

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
Detection of Small GTPase Prenylation and GTP Binding Using Membrane Fractionation and GTPase-linked Immunosorbent Assay13:51

Detection of Small GTPase Prenylation and GTP Binding Using Membrane Fractionation and GTPase-linked Immunosorbent Assay

Published on: November 11, 2018

9.9K

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:
4.0K
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...
6.3K
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,...
8.4K
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...
7.3K
¹H NMR of Conformationally Flexible Molecules: Temporal Resolution00:52

¹H NMR of Conformationally Flexible Molecules: Temporal Resolution

At room temperature, the chair conformer of cyclohexane undergoes rapid ring flipping between two equivalent chair conformers at a rate of approximately 105 times per second. These two chair conformers are in equilibrium. The rapid ring flipping results in the interconversion of the axial proton to an equatorial proton and an equatorial to the axial proton. Such interconversions are too rapid and cannot be detected on the NMR timescale. Hence, the NMR spectrometer cannot distinguish between the...
893
Rab Cascades01:25

Rab Cascades

Rab GTPases act in a regulated cascade during membrane fusion, helping the lipid bilayers mix. The Rab family of proteins are active when bound to GTP, and inactive when bound to GDP. Hence, they act as guanine nucleotide-dependent molecular switches. Rab-GTP recognizes and binds to long or short-range tethering proteins to capture the target vesicle. These tethers coordinate with SNAREs on the vesicle and the target membrane to assemble the trans SNARE complex that locks the mixing bilayers.
2.7K