Related Experiment Video

Updated: Mar 10, 2026

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

6.6K

Energetics and structural characterization of the "DFG-flip" conformational transition of B-RAF kinase: a SITS

Qiang Shao1, Zhijian Xu1, Jinan Wang1

  • 1Drug Discovery and Design Center, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China. qshao@mail.shcnc.ac.cn.

Physical Chemistry Chemical Physics : PCCP
|December 15, 2016
PubMed

Insights

Researchers uncovered the molecular mechanism behind B-RAF protein kinase

Area of Science:

  • Biochemistry
  • Structural Biology
  • Computational Biology

Background:

  • B-RAF protein kinase is a key target for treating malignant melanoma.
  • Its activity is regulated by conformational changes, specifically the DFG-flip.
  • The precise mechanism of this transition remains elusive due to experimental challenges.

Purpose of the Study:

  • To elucidate the molecular mechanism of the B-RAF functional conformational transition.
  • To identify and energetically characterize the transition pathway on a free-energy landscape.
  • To provide insights for developing B-RAF inhibitors.

Main Methods:

  • Homology modeling techniques were employed.
  • Enhanced sampling molecular dynamics simulations were utilized.
  • Analysis focused on the multi-dimensional free-energy landscape.

Main Results:

  • The conformational transition of B-RAF was identified as a two-state process.
  • The free-energy barrier was calculated and found comparable to other kinases.
  • Hydrophobic interactions between the activation loop and adjacent segments were identified as key drivers.

Conclusions:

  • Hydrophobic interactions critically influence the B-RAF conformational transition and its energy barrier.
  • Understanding these interactions offers a potential strategy for B-RAF inhibitor development.
  • This study provides a detailed molecular perspective on B-RAF regulation.

More Related Videos

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation15:05

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

Published on: May 20, 2020

9.4K
Author Spotlight: Integrating BRET-Based Assays and Rare Mutation Analysis to Decipher RAF Kinase Regulation in Live Cells06:44

Author Spotlight: Integrating BRET-Based Assays and Rare Mutation Analysis to Decipher RAF Kinase Regulation in Live Cells

Published on: March 1, 2024

1.8K

Related Concept Videos

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...
8.9K
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:
5.6K