2W5B

Human Nek2 kinase ATPgammaS-bound

Summary for 2W5B

• Entry DOI: 10.2210/pdb2w5b/pdb
• Related: 2JAV 2W5A 2W5H
• Descriptor: SERINE/THREONINE-PROTEIN KINASE NEK2, PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: transferase, meiosis, mitosis, cytoplasm, metal-binding, phosphoprotein, nucleotide-binding, magnesium, cell cycle, atp-binding, centrosome splitting, cell division
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Nucleus. Isoform 1: Nucleus, nucleolus. Isoform 2: Cytoplasm: P51955
• Total number of polymer chains: 1
• Total formula weight: 33215.46

Authors

Bayliss, R. (deposition date: 2008-12-08, release date: 2008-12-23, Last modification date: 2024-05-08)

Primary citation

Westwood, I.,Cheary, D.M.,Baxter, J.E.,Richards, M.W.,Van Montfort, R.L.,Fry, A.M.,Bayliss, R.
Insights Into the Conformational Variability and Regulation of Human Nek2 Kinase.
J.Mol.Biol., 386:476-, 2009

PubMed 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.

PubMed: 19124027
DOI: 10.1016/J.JMB.2008.12.033

Experimental method

X-RAY DIFFRACTION (2.4 Å)