Structural Differences between Wild-Type and Double Mutant EGFR Modulated by Third-Generation Kinase Inhibitors.

Mutations in the EGFR kinase domain are implicated in non-small-cell lung cancer. Of particular interest is the drug-resistant double mutant (L858R/T790M, DM EGFR), which is not inhibited selectively by any approved kinase inhibitor. Here we apply bipartite tetracysteine display to demonstrate that DM and WT EGFR differ in structure outside the kinase domain.

Bipartite tetracysteine display reveals allosteric control of ligand-specific EGFR activation.

Aberrant activation of the epidermal growth factor receptor (EGFR), a prototypic receptor tyrosine kinase, is critical to the biology of many common cancers. The molecular events that define how EGFR transmits an extracellular ligand binding event through the membrane are not understood. Here we use a chemical tool, bipartite tetracysteine display, to report on ligand-specific conformational changes that link ligand binding and kinase activation for full-length EGFR on the mammalian cell surface.

Visualizing protein partnerships in living cells and organisms.

In recent years, scientists have expanded their focus from cataloging genes to characterizing the multiple states of their translated products. One anticipated result is a dynamic map of the protein association networks and activities that occur within the cellular environment. While in vitro-derived network maps can illustrate which of a multitude of possible protein-protein associations could exist, they supply a falsely static picture lacking the subtleties of subcellular location (where) or cellular state (when).

Tandem C-C bond-forming processes: interception of the pd-catalyzed decarboxylative allylation of allyl diphenylglycinate imines with activated olefins.

Interception of the Pd-catalyzed decarboxylative allylation of allyl diphenylglycinate imines with appropriately functionalized Michael acceptors, followed by Heck cyclization, allows for the efficient construction of relatively complex organoamine frameworks in one reaction vessel. The initial intercepted decarboxylative allylation is remarkably insensitive toward solvent and catalyst, typically proceeding under ambient conditions.