In this section
@article{Gilburt:2019:10.1039/c8sc03669a,
author = {Gilburt, J and Girvan, P and Blagg, J and Ying, L and Dodson, CA},
doi = {10.1039/c8sc03669a},
journal = {Chemical Science},
pages = {4069--4076},
title = {Ligand discrimination between active and inactive activation loop conformations of Aurora-A kinase is unmodified by phosphorylation},
url = {http://dx.doi.org/10.1039/c8sc03669a},
volume = {10},
year = {2019}
}
TY - JOUR
AB - Structure-based drug design is commonly used to guide the development of potent and specific enzyme inhibitors. Many enzymes – such as protein kinases – adopt multiple conformations, and conformational interconversion is expected to impact on the design of small molecule inhibitors. We measured the dynamic equilibrium between DFG-in-like active and DFG-out-like inactive conformations of the activation loop of unphosphorylated Aurora-A alone, in the presence of the activator TPX2, and in the presence of kinase inhibitors. The unphosphorylated kinase had a shorter residence time of the activation loop in the active conformation and a shift in the position of equilibrium towards the inactive conformation compared with phosphorylated kinase for all conditions measured. Ligand binding was associated with a change in the position of conformational equilibrium which was specific to each ligand and independent of the kinase phosphorylation state. As a consequence of this, the ability of a ligand to discriminate between active and inactive activation loop conformations was also independent of phosphorylation. Importantly, we discovered that the presence of multiple enzyme conformations can lead to a plateau in the overall ligand Kd, despite increasing affinity for the chosen target conformation, and modelled the conformational discrimination necessary for a conformation-promoting ligand.
AU - Gilburt,J
AU - Girvan,P
AU - Blagg,J
AU - Ying,L
AU - Dodson,CA
DO - 10.1039/c8sc03669a
EP - 4076
PY - 2019///
SN - 2041-6520
SP - 4069
TI - Ligand discrimination between active and inactive activation loop conformations of Aurora-A kinase is unmodified by phosphorylation
T2 - Chemical Science
UR - http://dx.doi.org/10.1039/c8sc03669a
UR - http://hdl.handle.net/10044/1/68971
VL - 10
ER -
