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Journal Article

Studying the conformation of a receptor tyrosine kinase in solution by inhibitor-based spin labeling

MPS-Authors

Yin,  DongshengM.
Max Planck Fellow Chemical Biology, Center of Advanced European Studies and Research (caesar), Max Planck Society;

Schmitz,  Anton
Max Planck Fellow Chemical Biology, Center of Advanced European Studies and Research (caesar), Max Planck Society;

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Famulok,  Michael
Max Planck Fellow Chemical Biology, Center of Advanced European Studies and Research (caesar), Max Planck Society;

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Citation

Yin, D., Hannam, J. S., Schmitz, A., Schiemann, O., Hagelueken, G., & Famulok, M. (2017). Studying the conformation of a receptor tyrosine kinase in solution by inhibitor-based spin labeling. Angewandte Chemie International Edition in English, 56(29), 8417-8421. doi:10.1002/anie.201703154.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002D-8C4E-3
Abstract
The synthesis of a spin label based on PD168393, a covalent inhibitor of a major anticancer drug target, the epidermal growth factor receptor (EGFR), is reported. The label facilitates the analysis of the EGFR structure in solution by pulsed electron paramagnetic resonance (EPR) spectroscopy. For various EGFR constructs, including near-full-length EGFR, we determined defined distance distributions between the two spin labels bound to the ATP binding sites of the EGFR dimer. The distances are in excellent agreement with an asymmetric dimer of the EGFR. Based on crystal structures, this dimer had previously been proposed to reflect the active conformation of the receptor but structural data demonstrating its existence in solution have been lacking. More generally, our study provides proof-of-concept that inhibitor-based spin labeling enables the convenient introduction of site-specific spin labels into kinases for which covalent or tight-binding small-molecule modulators are available.