PDBsum entry 2z7r

Transferase

PDB id: 2z7r

Contents

Protein chain

265 a.a. *

Ligands

STU

Waters ×107

* Residue conservation analysis

PDB id:

2z7r

Name:

Transferase

Title:

Crystal structure of the n-terminal kinase domain of human rsk1 bound to staurosporine

Structure:

Ribosomal protein s6 kinase alpha-1. Chain: a. Fragment: residues 33-353. Synonym: s6k-alpha 1, 90 kda ribosomal protein s6 kinase 1, p90-rsk 1, ribosomal s6 kinase 1, rsk-1, pp90rsk1, p90s6k, map kinase- activated protein kinase 1a, mapkapk1a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: rps6ka1, rsk1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf21

Resolution:

2.00Å R-factor: 0.255 R-free: 0.286

Authors:

M.Ikuta,S.K.Munshi

Key ref:

M.Ikuta et al. (2007). Crystal structures of the N-terminal kinase domain of human RSK1 bound to three different ligands: Implications for the design of RSK1 specific inhibitors. Protein Sci, 16, 2626-2635. PubMed id: 17965187 DOI: 10.1110/ps.073123707

Date:

28-Aug-07 Release date: 13-May-08

Protein chain

Q15418  (KS6A1_HUMAN) -  Ribosomal protein S6 kinase alpha-1 from Homo sapiens

Seq: 735 a.a.

Struc: 265 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: 10.1110/ps.073123707

Protein Sci 16:2626-2635 (2007)

PubMed id: 17965187

Crystal structures of the N-terminal kinase domain of human RSK1 bound to three different ligands: Implications for the design of RSK1 specific inhibitors.

M.Ikuta, M.Kornienko, N.Byrne, J.C.Reid, S.Mizuarai, H.Kotani, S.K.Munshi.

ABSTRACT

The p90 ribosomal S6 kinases (RSKs) also known as MAPKAP-Ks are serine/threonine protein kinases that are activated by ERK or PDK1 and act as downstream effectors of mitogen-activated protein kinase (MAPK). RSK1, a member of the RSK family, contains two distinct kinase domains in a single polypeptide chain, the regulatory C-terminal kinase domain (CTKD) and the catalytic N-terminal kinase domain (NTKD). Autophosphorylation of the CTKD leads to activation of the NTKD that subsequently phosphorylates downstream substrates. Here we report the crystal structures of the unactivated RSK1 NTKD bound to different ligands at 2.0 A resolution. The activation loop and helix alphaC, key regulatory elements of kinase function, are disordered. The DFG motif of the inactive RSK1 adopts an "active-like" conformation. The beta-PO(4) group in the AMP-PCP complex adopts a unique conformation that may contribute to inactivity of the enzyme. Structures of RSK1 ligand complexes offer insights into the design of novel anticancer agents and into the regulation of the catalytic activity of RSKs.

Selected figure(s)

Figure 1.
Domain organization of RSKs. RSK1 has two kinase domains that can be activated by ERK and PDK1. The current model for activation suggests that, following mitogen stimulation, ERK phosphorylates Thr573, which is located in the activation loop of the CTKD of RSK1, and Thr359 and Ser363, which are in the linker region of RSK1 (Gavin and Nebreda 1999; Smith et al. 1999). Activation of the CTKD by ERK leads to autophosphorylation of Ser380 which is also located in the linker region. Ser380 is located in a hydrophobic motif conserved among a large number of the AGC family kinases. The result is a conformational alteration of RSK1, creating a docking site for PDK1, which then fully activates RSK1 by phosphorylation of Ser221 in the activation loop of the NTKD.

Figure 3.
Close-up view of the ATP-binding site. (A) Stereoview of RSK1 with bound AMP --PCP. Magnesium ion is shown as a green sphere. The P-loop is colored green. (B) 2Fo[minus sign]Fc map contoured at 1.5[sigma] for AMP --PCP bound to RSK1. (C) Superimposed AMP --PCP of RSK1 (green) and AMP --PNP in unphosphorylated EphA2 (cyan) (PDB code 1MQB). The Mg^2+ ion bound to RSK1 is shown as a magenta-colored sphere. (D) Superimposed AMP --PCP of RSK1 (green) and ATP in active PKA (gray) (PDB code 1ATP). Two Mg^2+ ions bound to PKA are shown as a purple-colored sphere. (E) Superimposed ATP of PKA (gray) and AMP --PNP in unphosphorylated EphA2 (cyan). In the inactive RSK1 structure, the sugar ring is in a different conformation compared to EphA2 and PKA. The phosphate groups in PKA and EphA2 are similarly oriented. However, [beta]-phosphate in RSK1 meanders in an opposite direction.

The above figures are reprinted from an Open Access publication published by the Protein Society: Protein Sci (2007, 16, 2626-2635) copyright 2007.

Figures were selected by an automated process.