Sequence-selective molecular recognition of the C-terminal CaaX-boxes of Rheb and related Ras-proteins by synthetic

Related Experiment Video

Updated: Apr 29, 2026

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans
08:12

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans

Published on: October 5, 2020

2.4K

Peter M Düppe1, Thao Tran Thi Phuong, Jasmin Autzen

  • 1University of Wuppertal , Gaußstraße 20, D-42119 Wuppertal, Germany.

ACS Chemical Biology
|May 27, 2014
PubMed

Insights

Researchers developed a novel approach to inhibit Ras-proteins, crucial in aggressive cancers. By masking the C-terminal CaaX-box, they aim to block membrane insertion and disrupt protein interactions, offering a new therapeutic strategy for cancer treatment.

Area of Science:

  • Molecular Biology
  • Oncology
  • Drug Discovery

Background:

  • Constitutive activation of Ras-proteins is a key driver in aggressive colorectal carcinomas and other cancers.
  • Targeting Ras-proteins, particularly Rheb, remains challenging due to the lack of efficient small molecule inhibitors that disrupt its interaction with mTOR.

Purpose of the Study:

  • To develop a novel therapeutic strategy targeting Ras-protein membrane insertion.
  • To identify inhibitors that mask the C-terminal CaaX-box of Rheb and related Ras proteins.

Main Methods:

  • Utilized a complementary approach focusing on inhibiting membrane insertion of Ras proteins.
  • Employed combinatorial solid-phase libraries to identify peptidomimetic receptors.
  • Screened for molecules that mask the C-terminal CaaX-box of Rheb.

Main Results:

  • Successfully identified peptidomimetic receptors capable of masking the C-terminal CaaX-box.
  • This approach aims to inhibit the membrane insertion of Rheb and related Ras proteins.

Conclusions:

  • The developed strategy offers a promising new avenue for inhibiting Ras-protein function in cancer.
  • Masking the CaaX-box represents a viable alternative to direct inhibition of Ras-protein interactions.

More Related Videos

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

1.9K
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

10.3K

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...
7.3K
Rab Proteins01:14

Rab Proteins

Rab proteins constitute the largest family of monomeric GTPases, of which 70 members are present in humans. Rab proteins and their effectors regulate consecutive stages of vesicle transport such as vesicle transport, docking, and fusion to the correct recipient membrane.
Rab proteins switch between a cytosolic, GDP-bound inactive state and a membrane-anchored, GTP-bound active state. By themselves, Rabs show slow rates of GDP/GTP exchange and GTP hydrolysis. Thus, Rab proteins are considered...
4.0K
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.
2.8K
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:
4.4K
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...
5.7K
Assembly of Signaling Complexes01:30

Assembly of Signaling Complexes

Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
4.7K