Well, your best chances are with existing monoclonal antibodies binding extracellular domain stronger than the native ligands and interfering with binding of those ligands- like Cetuximab (C225, Erbitux™) –chimeric counterpart of the murine monoclonal antibody M225 or Panitumumab. The catch (and there is one, as always) is that such binding often induce internalization of the receptor, so the outcome will be somewhat messy I suspect. But I never tried myself, so can't tell if it will work or not. I'm afraid, as it is often in biology, there is only one way to find out - to actually do it. Hope it works for you!

Hi Daisy - as Vadim has said if you use i.e. antibdodies you can actually induce dimerisation (activation and/or internalisaion).

I had a quick look and came across the following paper - it mentions Argos as an EGF antagonist.

Article Evidence that Argos is an antagonistic ligand of the EGF receptor

Another possibilty might be saturating the media with a peptide that binds the extra-cellular domain (and hope it will out-compete EGF without causing EGFR ativation). Alternatively you could saturate the media with the extra-cellular domain of the receptor itself (to soak up any EGF ligand floating around).

When I worked with the M-CSF receptor (long, long ago) we found that the commonly used method of making "kinase dead" mutants by mutating an invariant lysine residue prevented receptor internalisation - not due to the fact that it killed the recpetor activity - but probably because it prevented the conformational changes required for internalisation (other kinase dead mutants could internalise).

https://www.nature.com/articles/1202743

This is a long-winded way of saying that by mutating the invariant lysine in EGFR you may prevent the internalisation and auto-phosphorylation (after ligand binding) but hopefullly still have the intracellular targets available for phosphorylation by other proteins (I hope that makes sense - there are refs to the EGFR mutants in the paper link)

Note: If your target is in the a-loop (activation loop defined by the amino acids DGF...APE then it will be unlikely to be availabel for phosphorylation in the kinase dead mutant).

Hope this helped

Gary

note: that should be "DFG... APE" not DGF!