PDBsum entry: 1gzk

Kinase

PDB id: 1gzk

Contents

Protein chain

271 a.a. *

Waters ×284

* Residue conservation analysis

PDB id:

1gzk

Name:

Kinase

Title:

Molecular mechanism for the regulation of protein kinase b/ akt by hydrophobic motif phosphorylation

Structure:

Rac-beta serine/threonine protein kinase. Chain: a. Fragment: kinase domain, residues (146 - 460). Synonym: protein kinase akt-2, protein kinase b beta, rac-pk-beta, pkb beta. Engineered: yes

Source:

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

Resolution:

2.3Å R-factor: 0.248 R-free: 0.319

Authors:

D.Barford,J.Yang,B.A.Hemmings

Key ref:

J.Yang et al. (2002). Molecular mechanism for the regulation of protein kinase B/Akt by hydrophobic motif phosphorylation. Mol Cell, 9, 1227-1240. PubMed id: 12086620 DOI: 10.1016/S1097-2765(02)00550-6

Date:

23-May-02 Release date: 22-May-03

Protein chain

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

Seq: 481 a.a.

Struc: 271 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.11.1 - Non-specific serine/threonine protein kinase.
• Reaction: ATP + a protein = ADP + a phosphoprotein

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

 Gene Ontology (GO) functional annotation 

• Biological process: protein amino acid phosphorylation (1 term)
• Biochemical function: protein kinase activity (3 terms)

reference

DOI no: 10.1016/S1097-2765(02)00550-6

Mol Cell 9:1227-1240 (2002)

PubMed id: 12086620

Molecular mechanism for the regulation of protein kinase B/Akt by hydrophobic motif phosphorylation.

J.Yang, P.Cron, V.Thompson, V.M.Good, D.Hess, B.A.Hemmings, D.Barford.

ABSTRACT

Protein kinase B/Akt plays crucial roles in promoting cell survival and mediating insulin responses. The enzyme is stimulated by phosphorylation at two regulatory sites: Thr 309 of the activation segment and Ser 474 of the hydrophobic motif, a conserved feature of many AGC kinases. Analysis of the crystal structures of the unphosphorylated and Thr 309 phosphorylated states of the PKB kinase domain provides a molecular explanation for regulation by Ser 474 phosphorylation. Activation by Ser 474 phosphorylation occurs via a disorder to order transition of the alphaC helix with concomitant restructuring of the activation segment and reconfiguration of the kinase bilobal structure. These conformational changes are mediated by a phosphorylation-promoted interaction of the hydrophobic motif with a channel on the N-terminal lobe induced by the ordered alphaC helix and are mimicked by peptides corresponding to the hydrophobic motif of PKB and potently by the hydrophobic motif of PRK2.

Selected figure(s)

Figure 3.
Figure 3. Role of αC Helix to Regulate Conformation of PKA and PKB and Structure of Activation Segment and DFG Motif(A) αC helix stabilizes an active state of PKA by interaction with pThr 197 of the activation segment via His 87, and Phe 185 of the DFG motif via Ile 93 and Leu 94.(B) In PKB, disorder of the αC helix prevents His 196 from interacting with pThr 309; Phe 294 of the DFG motif binds within the nucleotide binding site of ATP.

Figure 7.
Figure 7. Conserved Residues of the Hydrophobic Motif, and Residues of the N Lobe of PKB, Are Required for PIFtide and PKB HM Peptide-Mediated Stimulation of PKB Kinase Activity(A) Mutations of conserved hydrophobic motif residues of PIFtide and PKB HM peptide reduce or eliminate their potential to activate ΔPH-PKB-ΔC phosphorylated on Thr 309.(B) Mutations of hydrophobic and electrostatic residues of the ΔPH-PKB-ΔC N lobe hydrophobic groove reduces the stimulation of PKB activity by 130 μM PIFtide. The positions of mutated residues on PKA and PKB (R202D, V194A-V198A, and L225A) are shown colored pink in Figures 2B and 2C and shown in Figure 5.

The above figures are reprinted by permission from Cell Press: Mol Cell (2002, 9, 1227-1240) copyright 2002.

Figures were selected by an automated process.