PDBsum entry 2jav

Transferase

PDB id: 2jav

Contents

Protein chain

253 a.a. *

Ligands

5Z5

Waters ×107

* Residue conservation analysis

PDB id:

2jav

Name:

Transferase

Title:

Human kinase with pyrrole-indolinone ligand

Structure:

Serine/threonine-protein kinase nek2. Chain: a. Fragment: kinase domain, residues 1-271. Synonym: nima-related protein kinase 2, nima-like protein kinase 1, hspk 21, never in mitosis gene a-related kinase 2. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Biol. unit:

Monomer (from PDB file)

Resolution:

2.20Å R-factor: 0.217 R-free: 0.277

Authors:

A.C.W.Pike,P.Rellos,S.Das,O.Fedorov,E.Papagrigoriou,J.E.Debreczeni, A.P.Turnbull,F.Gorrec,J.Bray,M.Sundstrom,C.H.Arrowsmith,A.Edwards, J.Weigelt,F.Von Delft,S.Knapp

Key ref:

P.Rellos et al. (2007). Structure and regulation of the human Nek2 centrosomal kinase. J Biol Chem, 282, 6833-6842. PubMed id: 17197699 DOI: 10.1074/jbc.M609721200

Date:

30-Nov-06 Release date: 04-Dec-06

Supersedes:

2cl1

Protein chain

P51955  (NEK2_HUMAN) -  Serine/threonine-protein kinase Nek2 from Homo sapiens

Seq: 445 a.a.

Struc: 253 a.a.*

* PDB and UniProt seqs differ at 8 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1074/jbc.M609721200

J Biol Chem 282:6833-6842 (2007)

PubMed id: 17197699

Structure and regulation of the human Nek2 centrosomal kinase.

P.Rellos, F.J.Ivins, J.E.Baxter, A.Pike, T.J.Nott, D.M.Parkinson, S.Das, S.Howell, O.Fedorov, Q.Y.Shen, A.M.Fry, S.Knapp, S.J.Smerdon.

ABSTRACT

The dimeric Ser/Thr kinase Nek2 regulates centrosome cohesion and separation through phosphorylation of structural components of the centrosome, and aberrant regulation of Nek2 activity can lead to aneuploid defects characteristic of cancer cells. Mutational analysis of autophosphorylation sites within the kinase domain identified by mass spectrometry shows a complex pattern of positive and negative regulatory effects on kinase activity that are correlated with effects on centrosomal splitting efficiency in vivo. The 2.2-A resolution x-ray structure of the Nek2 kinase domain in complex with a pyrrole-indolinone inhibitor reveals an inhibitory helical motif within the activation loop. This helix presents a steric barrier to formation of the active enzyme and generates a surface that may be exploitable in the design of specific inhibitors that selectively target the inactive state. Comparison of this "auto-inhibitory" conformation with similar arrangements in cyclin-dependent kinase 2 and epidermal growth factor receptor kinase suggests a role for dimerization-dependent allosteric regulation that combines with autophosphorylation and protein phosphatase 1c phosphatase activity to generate the precise spatial and temporal control required for Nek2 function in centrosomal maturation.

Selected figure(s)

Figure 1.
FIGURE 1. Structure and autophosphorylation of human Nek2. A, schematic showing the major structural and functional features Nek2A organization. Sites of autophosphorylation within both the catalytic and C-terminal regions are shown. PP1c, protein phosphatase 1c. B, a section of the 2F[o] - F[c] electron density map around the SU11652 inhibitor, contoured at 1 . C, structure of the Nek2 kinase domain-SU11652 complex. The N and C lobes are colored blue and red, respectively, the hinge region is highlighted in yellow, and the inhibitor is shown in green. Regions of disorder in the structure are included as dashed lines. D, phylogenetic tree showing the sequence relationships between the eleven human Nek-family members.

Figure 3.
FIGURE 3. Structural basis of inhibition. The SU11652 inhibitor interacts with the ATP binding cleft through a network of hydrogen-bonding interactions with main-chain atoms from the kinase hinge region and van der Waals interactions with residues from the N and C lobe together with Leu-162 from the T helix. The structure of the inhibitor is shown in the inset. The (diethylamino)ethyl moiety (highlighted) is disordered in the crystal structure.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2007, 282, 6833-6842) copyright 2007.

Figures were selected by the author.