Rotational Resonance NMR Structural Studies of the new Receptor TransmembraneDomain

摘要

The objective of this Exploratory Award was to establish whether magic anglespinning NMR and polarized infrared Spectroscopy could be applied to obtain high resolution structural constraints on the transmembrane domain of the neu/erbB-2 receptor in membrane environments. Such data would be able to address specific models for receptor activation by the transforming glutamic acid 664 mutation. The ultimate goal has been to obtain a high resolution 3D structure of the transmembrane domain of the constitutively activated receptor that can be used to establish the activation mechanism and possibly serve as a guide to the design of competitive inhibitors. The results obtained to date demonstrate that the approach outlined was successful and has provided the ground work for further studies. The major conclusion that can be drawn thus far is that the valine to glutamic acid mutation that activates the neu receptor, and is associated with a large number of breast cancers, functions by stabilizing receptor dimers via strong head-to-head hydrogen bonding interactions of the protonated glutamic acid COOH side chain.