Abstract
Monopolar spindle 1 (Mps1) is a dual‐specificity protein kinase, orchestrating faithful chromosome segregation during mitosis. All reported structures of the Mps1 kinase adopt the hallmarks of an inactive conformation, which includes a mostly disordered activation loop. Here, we present a 2.4 Å resolution crystal structure of an “extended” version of the Mps1 kinase domain, which shows an ordered activation loop. However, the other structural characteristics of an active kinase are not present. Our structure shows that the Mps1 activation loop can fit to the ATP binding pocket and interferes with ATP, but less so with inhibitors binding, partly explain the potency of various Mps1 inhibitors.
Highlights
Cell division is one of the most dynamic processes in cell cycle, and is orchestrated by a series of highly regulated events
To investigate whether the Mps1 degradation signal (MDS) region is interfering with the kinase domain structurally, we crystallized Mps1400-808 in the presence of ATP
The crystal structure was determined by molecular replacement, at 2.4 Å resolution (Table 1 and Figure 1C−E)
Summary
Cell division is one of the most dynamic processes in cell cycle, and is orchestrated by a series of highly regulated events. We present the crystal structure of the Mps[1] kinase with an ordered activation loop. We explore the structure and compare of the Mps[1] kinase domain to previously reported structure models and discuss the functional significance of the activation loop.
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