Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/14461
Title: Insights into the conformational variability and regulation of human Nek2 kinase.
Authors: Westwood, I
Cheary, DM
Baxter, JE
Richards, MW
van Montfort RL
Fry, AM
Bayliss, R
First Published: 20-Feb-2009
Citation: J MOL BIOL, 2009, 386 (2), pp. 476-485
Abstract: The Nek family of serine/threonine kinases regulates centrosome and cilia function; in addition, several of its members are potential targets for drug discovery. Nek2 is dimeric, is cell cycle regulated and functions in the separation of centrosomes at G2/M. Here, we report the crystal structures of wild-type human Nek2 kinase domain bound to ADP at 1.55-A resolution and T175A mutant in apo form as well as that bound to a non-hydrolyzable ATP analog. These show that regions of the Nek2 structure around the nucleotide-binding site can adopt several different but well-defined conformations. None of the conformations was the same as that observed for the previously reported inhibitor-bound structure, and the two nucleotides stabilized two conformations. The structures suggest mechanisms for the auto-inhibition of Nek2 that we have tested by mutagenesis. Comparison of the structures with Aurora-A and Cdk2 gives insight into the structural mechanism of Nek2 activation. The production of specific inhibitors that target individual kinases of the human genome is an urgent challenge in drug discovery, and Nek2 is especially promising as a cancer target. We not only identify potential challenges to the task of producing Nek2 inhibitors but also propose that the conformational variability provides an opportunity for the design of Nek2 selective inhibitors because one of the conformations may provide a unique target.
DOI Link: 10.1016/j.jmb.2008.12.033
eISSN: 1089-8638
Links: http://hdl.handle.net/2381/14461
Type: Journal Article
Appears in Collections:Published Articles, Dept. of Biochemistry

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