Comparative Analysis of EGFR Tyrosine Kinase

3 min readNov 14, 2016

EGFR Tyrosine Kinase Comparison of Inactive and Active Mutatnt States

Protein Description

EGFR is an abbreviation for epidermal growth factor receptor, a member of the EGF family of extracellular receptors. The tyrosine kinase domain of this protein is the intracellular extension of the extracellular signally pathway. In the larger C-lobe of the kinase domain is a tyrosine residue that is crucial for signalling transduction.

EGFR macro molecule depiction of extracellular receptor and intracellular tyrosine kinase domain

Blocking activation of this residue is of significance, especially when the considering the frequency of mutation and propensity to cause cancers. Once blocked, EGFR will no allow Ca+ channels to stay open, preventing activation of downstream proteins involved with DNA transcription and cellular proliferation associated to cancer.

Exploring Protein Structure of EGFR Tyrosine Kinase

The media seen below were created from x-ray crystallography dataset sets of both EGFR in its inactive/inhibited state as well as a mutated EGFR in an active state.

3D Visualization of x-ray crystallography dataset PDB ID: 4HJO

EGFR becomes inactivated by pharmacological inhibitors by competitively binding to the ATP binding pocket of the TK domain. This causes subtle conformation changes in the protein preventing it to signal for cellular proliferation.

Data Visualization

The Tyrosine Kinase domain is composed of 2 major lobes, N and C. Important structures that determine it’s ultimate conformation and funciton are the C-helix, P-Loop and A-loop. Kinase domains of all types shre these basic structural similarities. The upon inactivation, the A-Loop contracts towards the N-Lobe as Tyr845 (orange amino acid) becomes protected from phosphorylation. The P-loop plays an important part in stabilizing the A-loop next to the N-lobe by Phe699 (red amino acid) forming a salt bridge with the A-loop.

EGFR Tyrosine Kinase bound by inhibitor visualized as a transparent surface model revealing ribbon backbone‘s’ C-Helix, P-Loop, and A-Loop

When drugs bind to the Tyrosine Kinase domain, it triggers this contraction of the A-loop while simultaneously blocking the ATP binding site of the protein. It’s believed that some drugs may drugs exacerbate mutations putting too much force on specific residues resulting in mutation or structural changes that allow for activation.

EGFR Tyrosine Kinase Mutations

Mutations happen. Unfortunately, sometimes mutations occur and proteins become resistant to drugs that previously worked. EGFR Tyrosine Kinase is one of those proteins. It has a few very amino acids prone to mutation. Some are near binding sites of drugs, some are the active residues.

Data Visualization

When mutations occur in the A-loop, it destabilizes from the N-lobe and leaves the ATP binding site open for phosphorylation, even in the presence of an inhibitor. This allows for EGFR to dimerize, open Ca+ channels and activate transcription factors in the nucleus.

EGFR Tyrosine Kinase Mutant bound by inhibitor visualized as a transparent surface model revealing ribbon backbone‘s’ C-Helix, P-Loop, A-Loop, and mutation residues

Blocking signaling transmition of EGFR Tyrosine Kinase is a hot topic in pharmacology. Understanding mutations of this protein are an important part of designing new drugs as mutations continue to occur. Visualizations of protein data like this is an important part of structure based drug design.