PDBsum entry 2c30

Transferase

PDB id: 2c30

Contents

Protein chain

290 a.a. *

Ligands

PO4

Metals

_CL

Waters ×350

* Residue conservation analysis

PDB id:

2c30

Name:

Transferase

Title:

Crystal structure of the human p21-activated kinase 6

Structure:

Serine/threonine-protein kinase pak 6. Chain: a. Fragment: kinase domain, residues 383-681. Synonym: p21-activated kinase 6, pak-6, pak-5. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.60Å R-factor: 0.198 R-free: 0.222

Authors:

P.Filippakopoulos,G.Berridge,J.Bray,N.Burgess,S.Colebrook,S.Das, J.Eswaran,O.Gileadi,E.Papagrigoriou,P.Savitsky,C.Smee,A.Turnbull, M.Sundstrom,C.Arrowsmith,J.Weigelt,A.Edwards,F.Von Delft,S.Knapp

Key ref:

J.Eswaran et al. (2007). Crystal Structures of the p21-activated kinases PAK4, PAK5, and PAK6 reveal catalytic domain plasticity of active group II PAKs. Structure, 15, 201-213. PubMed id: 17292838 DOI: 10.1016/j.str.2007.01.001

Date:

02-Oct-05 Release date: 08-Feb-06

Protein chain

Q9NQU5  (PAK6_HUMAN) -  Serine/threonine-protein kinase PAK 6 from Homo sapiens

Seq: 681 a.a.

Struc: 290 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.str.2007.01.001

Structure 15:201-213 (2007)

PubMed id: 17292838

Crystal Structures of the p21-activated kinases PAK4, PAK5, and PAK6 reveal catalytic domain plasticity of active group II PAKs.

J.Eswaran, W.H.Lee, J.E.Debreczeni, P.Filippakopoulos, A.Turnbull, O.Fedorov, S.W.Deacon, J.R.Peterson, S.Knapp.

ABSTRACT

p21-activated kinases have been classified into two groups based on their domain architecture. Group II PAKs (PAK4-6) regulate a wide variety of cellular functions, and PAK deregulation has been linked to tumor development. Structural comparison of five high-resolution structures comprising all active, monophosphorylated group II catalytic domains revealed a surprising degree of domain plasticity, including a number of catalytically productive and nonproductive conformers. Rearrangements of helix alphaC, a key regulatory element of kinase function, resulted in an additional helical turn at the alphaC N terminus and a distortion of its C terminus, a movement hitherto unseen in protein kinases. The observed structural changes led to the formation of interactions between conserved residues that structurally link the glycine-rich loop, alphaC, and the activation segment and firmly anchor alphaC in an active conformation. Inhibitor screening identified six potent PAK inhibitors from which a tri-substituted purine inhibitor was cocrystallized with PAK4 and PAK5.

Selected figure(s)

Figure 3.
Figure 3. Binding of the Purine Inhibitor
(A and B) Superimposition of PAK4 and PAK5 showing the (A) binding modes of the purine inhibitor and (B) interaction with active site residues in PAK4. A superimposition of the C-terminal lobes was used to generate the figure shown in (A). PAK4 is shown in yellow, and PAK5 is shown in orange.

Figure 5.
Figure 5. Rearrangement of Helix αC
(A) Superimposition of central residues in the PAK5 αC helices showing the remodeling of the αC termini. The central residues stay in position, whereas conversion into an active state (PAK5 purine complex) results in the addition of an N-terminal α helix and disruption of the αC terminus.
(B) Structural changes at the αC C terminus brings Asn493 (Asn365, PAK4) into position to hydrogen bond with the DFG glycine (Gly588) and a conserved activation segment cysteine (Cys590 and Cys462 in PAK5 and PAK4, respectively), resulting in the formation of the αC anchor point with the activation segment. In the PAK4 structures, this movement is not completed, and only one hydrogen bond is formed with Cys462.
(C) Swinging movement of the conserved αC Arg487 (Arg359 in PAK4) between the glycine-rich loop and the phosphoserine activation loop residue. Upon extension of the αC helix by one turn at the N –terminus, Arg487 forms three hydrogen bonds with the glycine-rich loop, stabilizing an extremely closed conformation (PAK5 purine complex, orange). In the short αC conformation, the corresponding arginine in PAK4 interacts with the phosphoserine residue in the activation segment. This conformation also results in a partially open conformation of the glycine-rich loop stabilized by a hydrogen bond formed by the conserved Gln357. When αC swings away (as observed in apo-PAK5, cyan, or PAK6 [not shown]), the N- and C-terminal anchor points break, resulting in an open glycine-rich loop conformation. During the swinging movement, Arg487 in the PAK5 apo structure was observed in a disordered state beyond the γ carbon (indicated by white balls and sticks).

The above figures are reprinted from an Open Access publication published by Cell Press: Structure (2007, 15, 201-213) copyright 2007.

Figures were selected by the author.

Author's comment

p21 activated kinases have been classified into two groups based on their domain architecture. Group II PAKs (PAK4-6) regulate a wide variety of cellular functions and PAK deregulation has been linked to tumor development. Here, we report a new mechanism of kinase activation revealed by comparison of five high-resolution structures comprising all group II family members. Structural comparison revealed a rearrangement of helix alpha-C, a key regulatory element of kinase function resulting in an additional helical turn at the alpha-C N-terminus and a distortion the alpha-C C-terminus, a movement hitherto unseen in protein kinases. The observed structural changes led to the formation of interactions between conserved residues which structurally link the glycine rich loop, alpha-C and the activation segment and firmly anchor alpha-C in an active conformation.