PDBsum entry 2fum

Transferase

PDB id: 2fum

Contents

Protein chains

263 a.a. *

Ligands

MIX ×4

* Residue conservation analysis

PDB id:

2fum

Name:

Transferase

Title:

Catalytic domain of protein kinase pknb from mycobacterium tuberculosis in complex with mitoxantrone

Structure:

Probable serine/threonine-protein kinase pknb. Chain: a, b, c, d. Fragment: catalytic domain. Synonym: pknb ser/thr kinase. Engineered: yes

Source:

Mycobacterium tuberculosis h37rv. Organism_taxid: 83332. Strain: h37rv. Gene: pknb. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Biol. unit:

Tetramer (from PQS)

Resolution:

2.89Å R-factor: 0.221 R-free: 0.278

Authors:

A.Wehenkel,P.M.Alzari

Key ref:

A.Wehenkel et al. (2006). The structure of PknB in complex with mitoxantrone, an ATP-competitive inhibitor, suggests a mode of protein kinase regulation in mycobacteria. FEBS Lett, 580, 3018-3022. PubMed id: 16674948 DOI: 10.1016/j.febslet.2006.04.046

Date:

27-Jan-06 Release date: 01-Aug-06

Protein chains

P9WI81  (PKNB_MYCTU) -  Serine/threonine-protein kinase PknB from Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)

Seq: 626 a.a.

Struc: 263 a.a.

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: 10.1016/j.febslet.2006.04.046

FEBS Lett 580:3018-3022 (2006)

PubMed id: 16674948

The structure of PknB in complex with mitoxantrone, an ATP-competitive inhibitor, suggests a mode of protein kinase regulation in mycobacteria.

A.Wehenkel, P.Fernandez, M.Bellinzoni, V.Catherinot, N.Barilone, G.Labesse, M.Jackson, P.M.Alzari.

ABSTRACT

Mycobacterium tuberculosis PknB is an essential receptor-like protein kinase involved in cell growth control. Here, we demonstrate that mitoxantrone, an anthraquinone derivative used in cancer therapy, is a PknB inhibitor capable of preventing mycobacterial growth. The structure of the complex reveals that mitoxantrone partially occupies the adenine-binding pocket in PknB, providing a framework for the design of compounds with potential therapeutic applications. PknB crystallizes as a 'back-to-back' homodimer identical to those observed in other structures of PknB in complex with ATP analogs. This organization resembles that of the RNA-dependent protein kinase PKR, suggesting a mechanism for kinase activation in mycobacteria.

Selected figure(s)

Figure 2.
Fig. 2. Structure of the PknB-mitoxantrone complex. (a) Superposition of the PknB-mitoxantrone complex (in yellow) and the PknB-AMPPCP complex (1O6Y, in cyan). Note the movement of the Gly-rich loop (black arrow). (b) Observed (yellow) and predicted (thin lines) orientations of mitoxantrone within the adenosine-binding cavity (represented as a molecular surface). The electron density map for the inhibitor is contoured at 1σ. (c) Schematic view (represented as in Ref. [26]) of the PknB ATP-binding site showing hydrogen bonding interactions with both the inhibitor (in blue) and AMP-PCP (PDB code 1O6Y).

Figure 3.
Fig. 3. The conserved PknB homodimer. (a) Superposition of the two crystallographically independent homodimers from the PknB-mitoxantrone complex (in red and green) with those observed in the PknB-nucleotide complexes 1O6Y [3] (in blue) and 1MRU [4] (in yellow). (b) Overall view of the PknB monomer (rotated 90° along the vertical axis with respect to the right monomer in Fig. 3a), color-coded according to amino acid conservation (red: highly conserved) in 39 PknB-like protein sequences from 35 different bacterial species (Bacillus anthracis, B. cereus, B. clausii, B. licheniformis, B. subtilis, Bifidobacterium longum, Clostridium acetobutylicum, C. perfringens, C. tetani, Corynebacterium diphtheriae, C. efficiens, C. glutamicum, Enterococcus faecalis, Geobacillus kaustophilus, Lactobacillus acidophilus, L. johnsonii, Listeria monocytogenes, Mycobacterium avium, M. bovis, M. leprae, M. tuberculosis, Nocardia farcinica, Nocardioides, Leifsonia xyli, Oceanobacillus iheyensis, Propionibacterium acnes, Staphylococcus haemolyticus, S. saprophyticus, Streptococcus agalactiae, S. mutans, S. pyogenes, Streptomyces coelicolor, Symbiobacterium thermophilum, Thermoanaerobacter tengcongensis, Thermobifida fusca). (c) Comparison of the PknB and RNA-dependent PKR dimer interfaces. The side-chain residues belonging to the interfaces are shown (PknB color-coded as in (b)).

The above figures are reprinted by permission from the Federation of European Biochemical Societies: FEBS Lett (2006, 580, 3018-3022) copyright 2006.

Figures were selected by the author.