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Insights Into the Conformational Variability and Regulation of Human Nek2 Kinase.

DOI: 10.1016/j.jmb.2008.12.033 DOI Help
PMID: 19124027 PMID Help

Authors: Isaac Westwood (Institute of Cancer Research) , Donna-marie Cheary (University of Leicester) , Joanne Baxter (University of Leicester) , Mark Richards (Institute of Cancer Research) , Rob Van Montfort (Institute of Cancer Research) , Andrew Fry (University of Leicester) , Richard Bayliss (Institute of Cancer Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Molecular Biology , VOL 386 (2) , PAGES 476-485

State: Published (Approved)
Published: February 2009

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-Å 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.

Journal Keywords: Crystallography; X-Ray; Humans; Models; Molecular; Mutant; Mutation; Missense; Protein; Quaternary; Protein; Tertiary; Protein-Serine-Threonine Kinases

Subject Areas: Biology and Bio-materials

Instruments: I03-Macromolecular Crystallography

Added On: 04/08/2009 13:34

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