PDBsum entry 2f2u

Transferase

PDB id: 2f2u

Contents

Protein chains

386 a.a. *

Ligands

M77 ×2

Waters ×162

* Residue conservation analysis

PDB id:

2f2u

Name:

Transferase

Title:

Crystal structure of the rho-kinase kinase domain

Structure:

Rho-associated protein kinase 2. Chain: a, b. Fragment: protein kinase domain. Synonym: rho-associated, coiled- coil containing protein kinase 2, p164 rock-2. Engineered: yes

Source:

Bos taurus. Cattle. Organism_taxid: 9913. Gene: rock2. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Biol. unit:

Dimer (from PDB file)

Resolution:

2.40Å R-factor: 0.197 R-free: 0.235

Authors:

H.Yamaguchi,T.Hakoshima

Key ref:

H.Yamaguchi et al. (2006). Molecular mechanism for the regulation of rho-kinase by dimerization and its inhibition by fasudil. Structure, 14, 589-600. PubMed id: 16531242 DOI: 10.1016/j.str.2005.11.024

Date:

18-Nov-05 Release date: 25-Apr-06

Protein chains

Q28021  (ROCK2_BOVIN) -  Rho-associated protein kinase 2 from Bos taurus

Seq: 1388 a.a.

Struc: 386 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

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.str.2005.11.024

Structure 14:589-600 (2006)

PubMed id: 16531242

Molecular mechanism for the regulation of rho-kinase by dimerization and its inhibition by fasudil.

H.Yamaguchi, M.Kasa, M.Amano, K.Kaibuchi, T.Hakoshima.

ABSTRACT

Rho-kinase is a key regulator of cytoskeletal events and a promising drug target in the treatment of vascular diseases and neurological disorders. Unlike other protein kinases, Rho-kinase requires both N- and C-terminal extension segments outside the kinase domain for activity, although the details of this requirement have been elusive. The crystal structure of an active Rho-kinase fragment containing the kinase domain and both the extensions revealed a head-to-head homodimer through the N-terminal extension forming a helix bundle that structurally integrates the C-terminal extension. This structural organization enables binding of the C-terminal hydrophobic motif to the N-terminal lobe, which defines the correct disposition of helix alphaC that is important for the catalytic activity. The bound inhibitor fasudil significantly alters the conformation and, consequently, the mode of interaction with the catalytic cleft that contains local structural changes. Thus, both kinase and drug conformational pliability and stability confer selectivity.

Selected figure(s)

Figure 2.
Figure 2. Overall Structure of the Kinase Domain of Rho-Kinase and Comparison with PKA
(A) Ribbon diagram of Rho-kinase (molecules A). The kinase domain with the C-terminal extension is shown in cyan (N-terminal lobe), blue (C-terminal lobe), and red (C-terminal extension containing the hydrophobic motif). The N-terminal extension forming the CHB domain is omitted for clarity. All secondary structure elements are labeled. The bound fasudil is shown as a stick model. Five catalytically important residues (Lys121, Glu140, Asp214, Asn219, and Asp232) in addition to the potential phosphorylation site in the activation loop (Thr249) are shown. The functional motifs are shown with the same color scheme as in Figure 1A; magenta, P loop; orange, C loop; yellow, A loop. Dotted connections between the N-terminal lobe and the C-terminal extension are for residues omitted in model building due to poor electron density (see text).
(B) Ribbon diagram of PKA (PDB code: 1CDK). The bound ATP analog (AMPPNP) is shown as a stick model. Five catalytically important residues (Lys72, Glu91, Asp166, Asn171, and Asp184) and the phosphorylated threonine (pThr197) in the activation loop are shown. The functionally significant motifs are shown with the same color scheme as in (A). The PKI peptide is not shown for clarity.

The above figure is reprinted by permission from Cell Press: Structure (2006, 14, 589-600) copyright 2006.

Figure was selected by an automated process.