TY - JOUR
T1 - X-ray crystal structure of ERK5 (MAPK7) in complex with a specific inhibitor
AU - Elkins, Jonathan M.
AU - Wang, Jing
AU - Deng, Xianming
AU - Pattison, Michael J.
AU - Arthur, J. Simon C.
AU - Erazo, Tatiana
AU - Gomez, Nestor
AU - Lizcano, Jose M.
AU - Gray, Nathanael S.
AU - Knapp, Stefan
PY - 2013/6/13
Y1 - 2013/6/13
N2 - The 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. © 2013 American Chemical Society.
AB - The 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. © 2013 American Chemical Society.
U2 - https://doi.org/10.1021/jm4000837
DO - https://doi.org/10.1021/jm4000837
M3 - Article
VL - 56
SP - 4413
EP - 4421
ER -
