PDBsum entry 2jdo

Transferase

PDB id: 2jdo

Contents

Protein chain

315 a.a. *

Ligands

GLY-ARG-PRO-ARG-THR-THR-SER-PHE-ALA-GLU

I5S

EDO

Waters ×323

* Residue conservation analysis

PDB id:

2jdo

Name:

Transferase

Title:

Structure of pkb-beta (akt2) complexed with isoquinoline-5-sulfonic acid (2-(2-(4-chlorobenzyloxy) ethylamino)ethyl)amide

Structure:

Rac-beta serine/threonine-protein kinase. Chain: a. Fragment: kinase catalytic domain, residues 146-467. Synonym: protein kinase b-beta, rac-pk-beta, protein kinase akt-2, protein kinase b, beta, pkb beta. Engineered: yes. Other_details: piftide sequence (eeqemfedfdyiadw) replaces natural pkb sequence after residue 464. Glycogen synthase kinase-3 beta.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9. Synthetic: yes. Organism_taxid: 9606

Resolution:

1.80Å R-factor: 0.177 R-free: 0.210

Authors:

T.G.Davies,M.L.Verdonk,B.Graham,S.Saalau-Bethell,C.C.F.Hamlett, T.Mchardy,I.Collins,M.D.Garrett,P.Workman,S.J.Woodhead,H.Jhoti, D.Barford

Key ref:

T.G.Davies et al. (2007). A structural comparison of inhibitor binding to PKB, PKA and PKA-PKB chimera. J Mol Biol, 367, 882-894. PubMed id: 17275837 DOI: 10.1016/j.jmb.2007.01.004

Date:

11-Jan-07 Release date: 13-Feb-07

Protein chain

P31751  (AKT2_HUMAN) -  RAC-beta serine/threonine-protein kinase from Homo sapiens

Seq: 481 a.a.

Struc: 315 a.a.*

* PDB and UniProt seqs differ at 11 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: 10.1016/j.jmb.2007.01.004

J Mol Biol 367:882-894 (2007)

PubMed id: 17275837

A structural comparison of inhibitor binding to PKB, PKA and PKA-PKB chimera.

T.G.Davies, M.L.Verdonk, B.Graham, S.Saalau-Bethell, C.C.Hamlett, T.McHardy, I.Collins, M.D.Garrett, P.Workman, S.J.Woodhead, H.Jhoti, D.Barford.

ABSTRACT

Although the crystal structure of the anti-cancer target protein kinase B (PKBbeta/Akt-2) has been useful in guiding inhibitor design, the closely related kinase PKA has generally been used as a structural mimic due to its facile crystallization with a range of ligands. The use of PKB-inhibitor crystallography would bring important benefits, including a more rigorous understanding of factors dictating PKA/PKB selectivity, and the opportunity to validate the utility of PKA-based surrogates. We present a "back-soaking" method for obtaining PKBbeta-ligand crystal structures, and provide a structural comparison of inhibitor binding to PKB, PKA, and PKA-PKB chimera. One inhibitor presented here exhibits no PKB/PKA selectivity, and the compound adopts a similar binding mode in all three systems. By contrast, the PKB-selective inhibitor A-443654 adopts a conformation in PKB and PKA-PKB that differs from that with PKA. We provide a structural explanation for this difference, and highlight the ability of PKA-PKB to mimic the true PKB binding mode in this case.

Selected figure(s)

Figure 1.
Figure 1. Chemical structures of 1 (isoquinoline sulphonamide) and 2 (A-443654).

Figure 5.
Figure 5. Inhibitor 2 binding to PKA and PKB. (a) PKA-2 and (b) PKB-2 (in the region of the ATP site). Final 2mF[o]–DF[c] electron density for the inhibitors is contoured at 1σ and shown in blue. (c) Superposition of PKA-2 (grey) and PKB-2 (yellow). Residues are labelled using PKB numbering. (d) Schematic diagram showing binding of 2 to PKA and PKB. Key non-covalent interactions are depicted as broken lines. The alternative positions of the indole ring are shown by shading: PKA (light grey) and PKB (black). (e) Surface representation of PKB with compound 2 bound. The surface was coloured by lipophilicity in AstexViewer^46 using the method described by Gaillard et al.,^53 with red/pink representing the most lipophilic regions, and blue/green the least lipophilic. The putative methyl-aromatic interaction discussed in the text is shown as a broken line. (f) Overlay of surfaces for PKA (grey) and PKB (yellow) with compound 2 bound. The indole group of 2 packs with the side-chain of Met282, but would leave a cavity in PKA due to the substitution by leucine at this point in the active site.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2007, 367, 882-894) copyright 2007.

Figures were selected by an automated process.