Molecular dynamics simulation reveals structural and thermodynamic features of kinase activation by cancer mutations within the epidermal growth factor receptor

2011 ◽  
Vol 32 (13) ◽  
pp. 2843-2852 ◽  
Author(s):  
Shunzhou Wan ◽  
Peter V. Coveney
Keyword(s):  
Molecular Dynamics ◽  
Epidermal Growth Factor Receptor ◽  
Molecular Dynamics Simulation ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Dynamics Simulation ◽  
Kinase Activation ◽  
Cancer Mutations ◽  
Epidermal Growth

scholarly journals Structure-Based Drug Design Studies Toward the Discovery of Novel Chalcone Derivatives as Potential Epidermal Growth Factor Receptor (EGFR) Inhibitors

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3203 ◽  
Author(s):  
Menier Al-Anazi ◽  
Belal Al-Najjar ◽  
Melati Khairuddean
Keyword(s):  
Molecular Dynamics ◽  
Epidermal Growth Factor Receptor ◽  
Molecular Dynamics Simulation ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Active Site ◽  
Growth Factor Receptor ◽  
Dynamics Simulation ◽  
Chalcone Derivatives ◽  
Epidermal Growth

Human Epidermal Growth Factor Receptor-1 (EGFR), a transmembrane tyrosine kinase receptor (RTK), has been associated with several types of cancer, including breast, lung, ovarian, and anal cancers. Thus, the receptor was targeted by a variety of therapeutic approaches for cancer treatments. A series of chalcone derivatives are among the most highly potent and selective inhibitors of EGFR described to date. A series of chalcone derivatives were proposed in this study to investigate the intermolecular interactions in the active site utilizing molecular docking and molecular dynamics simulations. After a careful analysis of docking results, compounds 1a and 1d were chosen for molecular dynamics simulation study. Extensive hydrogen bond analysis throughout 7 ns molecular dynamics simulation revealed the ability of compounds 1a and 1d to retain the essential interactions needed for the inhibition, especially MET 93. Finally, MM-GBSA calculations highlight on the capability of the ligands to bind strongly within the active site with binding energies of −44.04 and −56.6 kcal/mol for compounds 1a and 1d, respectively. Compound 1d showed to have a close binding energy with TAK-285 (−66.17 kcal/mol), which indicates a high chance for compound 1d to exhibit inhibitory activity, thus recommending to synthesis it to test its biological activity. It is anticipated that the findings reported here may provide very useful information for designing effective drugs for the treatment of EGFR-related cancer disease.

scholarly journals Structural Evidence for Loose Linkage between Ligand Binding and Kinase Activation in the Epidermal Growth Factor Receptor

2010 ◽  
Vol 30 (22) ◽  
pp. 5432-5443 ◽  
Author(s):  
Chafen Lu ◽  
Li-Zhi Mi ◽  
Michael J. Grey ◽  
Jieqing Zhu ◽  
Elizabeth Graef ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Transmembrane Domains ◽  
Cross Linking ◽  
Hydrophobic Domain ◽  
Kinase Activation ◽  
Epidermal Growth

ABSTRACT The mechanisms by which signals are transmitted across the plasma membrane to regulate signaling are largely unknown for receptors with single-pass transmembrane domains such as the epidermal growth factor receptor (EGFR). A crystal structure of the extracellular domain of EGFR dimerized by epidermal growth factor (EGF) reveals the extended, rod-like domain IV and a small, hydrophobic domain IV interface compatible with flexibility. The crystal structure and disulfide cross-linking suggest that the 7-residue linker between the extracellular and transmembrane domains is flexible. Disulfide cross-linking of the transmembrane domain shows that EGF stimulates only moderate association in the first two α-helical turns, in contrast to association throughout the membrane over five α-helical turns in glycophorin A and integrin. Furthermore, systematic mutagenesis to leucine and phenylalanine suggests that no specific transmembrane interfaces are required for EGFR kinase activation. These results suggest that linkage between ligand-induced dimerization and tyrosine kinase activation is much looser than was previously envisioned.

scholarly journals A Brief History of Single-Particle Tracking of the Epidermal Growth Factor Receptor

2019 ◽  
Vol 2 (1) ◽  
pp. 12 ◽  
Author(s):  
David T. Clarke ◽  
Marisa L. Martin-Fernandez
Keyword(s):  
Molecular Dynamics ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Particle Tracking ◽  
Single Particle ◽  
Growth Factor Receptor ◽  
Single Particle Tracking ◽  
Epidermal Growth ◽  
And Function

Single-particle tracking (SPT) has been used and developed over the last 25 years as a method to investigate molecular dynamics, structure, interactions, and function in the cellular context. SPT is able to show how fast and how far individual molecules move, identify different dynamic populations, measure the duration and strength of intermolecular interactions, and map out structures on the nanoscale in cells. In combination with other techniques such as macromolecular crystallography and molecular dynamics simulation, it allows us to build models of complex structures, and develop and test hypotheses of how these complexes perform their biological roles in health as well as in disease states. Here, we use the example of the epidermal growth factor receptor (EGFR), which has been studied extensively by SPT, demonstrating how the method has been used to increase our understanding of the receptor’s organization and function, including its interaction with the plasma membrane, its activation, clustering, and oligomerization, and the role of other receptors and endocytosis. The examples shown demonstrate how SPT might be employed in the investigation of other biomolecules and systems.

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