jm4000837_si_001.pdf (2.22 MB)
X‑ray Crystal Structure of ERK5 (MAPK7) in Complex with a Specific Inhibitor
journal contribution
posted on 2015-12-16, 23:00 authored by Jonathan
M. Elkins, Jing Wang, Xianming Deng, Michael J. Pattison, J. Simon C. Arthur, Tatiana Erazo, Nestor Gomez, Jose M. Lizcano, Nathanael S. Gray, Stefan KnappThe
protein kinase ERK5 (MAPK7) is an emerging drug target for
a variety of indications, in particular for cancer where it plays
a key role mediating cell proliferation, survival, epithelial–mesenchymal
transition, and angiogenesis. To date, no three-dimensional structure
has been published that would allow rational design of inhibitors.
To address this, we determined the X-ray crystal structure of the
human ERK5 kinase domain in complex with a highly specific benzo[e]pyrimido[5,4-b]diazepine-6(11H)-one inhibitor. The structure reveals that specific residue
differences in the ATP-binding site, compared to the related ERKs
p38s and JNKs, allow for the development of ERK5-specific inhibitors.
The selectivity of previously observed ERK5 inhibitors can also be
rationalized using this structure, which provides a template for future
development of inhibitors with potential for treatment of disease.