Related Experiment Video

Updated: Sep 24, 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

Molecular basis for cooperative binding and synergy of ATP-site and allosteric EGFR inhibitors

Tyler S Beyett1,2, Ciric To3,4,5, David E Heppner1,2,6

  • 1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.

Nature Communications
|May 9, 2022
PubMed

Insights

New lung cancer therapies combine EGFR inhibitors for enhanced synergy. This approach overcomes resistance mutations, offering a promising strategy for improved patient outcomes in EGFR-mutated lung cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Activating mutations in epidermal growth factor receptor (EGFR) drive lung cancer.
  • Allosteric EGFR inhibitors show potential against resistance mutations and synergize with osimertinib.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying the synergy between ATP-competitive and allosteric EGFR inhibitors.
  • To identify specific irreversible EGFR inhibitors that exhibit cooperative binding and synergy with allosteric inhibitors.

Main Methods:

  • Combination studies of ATP-competitive and allosteric EGFR inhibitors.
  • Structural analysis of EGFR-inhibitor complexes.
  • Site-directed mutagenesis (F723 mutation) to probe binding mechanisms.

Main Results:

  • A subset of irreversible EGFR inhibitors demonstrated positive binding cooperativity and synergy with the allosteric inhibitor JBJ-04-125-02.
  • Structural analysis revealed key conformational changes in the phosphate-binding loop (P-loop).
  • Mutation of F723 in the P-loop diminished cooperative binding and synergy, highlighting its critical role.

Conclusions:

  • F723-mediated contacts between the P-loop and allosteric inhibitors are crucial for observed synergy.
  • These findings provide mechanistic insights for developing novel EGFR inhibitor combinations.
  • This research supports the development of new therapeutic strategies for EGFR-mutated lung cancer.

More Related Videos

Mapping the Binding Site of an Aptamer on ATP Using MicroScale Thermophoresis08:09

Mapping the Binding Site of an Aptamer on ATP Using MicroScale Thermophoresis

Published on: January 7, 2017

10.8K
Optimizing the Genetic Incorporation of Chemical Probes into GPCRs for Photo-crosslinking Mapping and Bioorthogonal Chemistry in Live Mammalian Cells14:02

Optimizing the Genetic Incorporation of Chemical Probes into GPCRs for Photo-crosslinking Mapping and Bioorthogonal Chemistry in Live Mammalian Cells

Published on: April 9, 2018

8.6K

Related Concept Videos

Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
8.1K
Allosteric Regulation01:08

Allosteric Regulation

Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...
59.4K
Ligand Binding and Linkage00:49

Ligand Binding and Linkage

Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked.  In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
5.0K
Allosteric Proteins-ATCase01:19

Allosteric Proteins-ATCase

Binding sites linkages can regulate a protein's function.  For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to  N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
5.9K
Transducer Mechanism: Enzyme-Linked Receptors01:27

Transducer Mechanism: Enzyme-Linked Receptors

Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
2.9K
Ligand Binding Sites02:40

Ligand Binding Sites

Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
13.6K