2XK3: Structure Of Nek2 Bound To Aminopyrazine Compound 35

Citation:
Abstract
We report herein the first systematic exploration of inhibitors of the mitotic kinase Nek2. Starting from HTS hit aminopyrazine 2, compounds with improved activity were identified using structure-based design. Our structural biology investigations reveal two notable observations. First, 2 and related compounds bind to an unusual, inactive conformation of the kinase which to the best of our knowledge has not been reported for other types of kinase inhibitors. Second, a phenylalanine residue at the center of the ATP pocket strongly affects the ability of the inhibitor to bind to the protein. The implications of these observations are discussed, and the work described here defines key features for potent and selective Nek2 inhibition, which will aid the identification of more advanced inhibitors of Nek2.
PDB ID: 2XK3Download
MMDB ID: 85706
PDB Deposition Date: 2010/7/7
Updated in MMDB: 2010/11
Experimental Method:
x-ray diffraction
Resolution: 2.2  Å
Source Organism:
Similar Structures:
Biological Unit for 2XK3: monomeric; determined by software (PISA)
Molecular Components in 2XK3
Label Count Molecule
Protein (1 molecule)
1
Serine/threonine-protein Kinase Nek2(Gene symbol: NEK2)
Molecule annotation
Chemicals (3 molecules)
1
1
2
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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