PDBsum entry 2c30

Go to PDB code: 
protein ligands metals links
Transferase PDB id
Jmol PyMol
Protein chain
290 a.a. *
Waters ×350
* Residue conservation analysis
PDB id:
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
1.60Å     R-factor:   0.198     R-free:   0.222
Authors: P.Filippakopoulos,G.Berridge,J.Bray,N.Burgess,S.Colebrook,S. J.Eswaran,O.Gileadi,E.Papagrigoriou,P.Savitsky,C.Smee,A.Tur M.Sundstrom,C.Arrowsmith,J.Weigelt,A.Edwards,F.Von Delft,S.
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
02-Oct-05     Release date:   08-Feb-06    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q9NQU5  (PAK6_HUMAN) -  Serine/threonine-protein kinase PAK 6
681 a.a.
290 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
+ protein
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     protein phosphorylation   1 term 
  Biochemical function     protein kinase activity     2 terms  


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.
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.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20439741 B.W.Murray, C.Guo, J.Piraino, J.K.Westwick, C.Zhang, J.Lamerdin, E.Dagostino, D.Knighton, C.M.Loi, M.Zager, E.Kraynov, I.Popoff, J.G.Christensen, R.Martinez, S.E.Kephart, J.Marakovits, S.Karlicek, S.Bergqvist, and T.Smeal (2010).
Small-molecule p21-activated kinase inhibitor PF-3758309 is a potent inhibitor of oncogenic signaling and tumor growth.
  Proc Natl Acad Sci U S A, 107, 9446-9451.
PDB code: 2x4z
20070256 C.M.Wells, and G.E.Jones (2010).
The emerging importance of group II PAKs.
  Biochem J, 425, 465-473.  
19854302 J.Eswaran, and S.Knapp (2010).
Insights into protein kinase regulation and inhibition by large scale structural comparison.
  Biochim Biophys Acta, 1804, 429-432.  
20124694 T.P.Ko, W.Y.Jeng, C.I.Liu, M.D.Lai, C.L.Wu, W.J.Chang, H.L.Shr, T.J.Lu, and A.H.Wang (2010).
Structures of human MST3 kinase in complex with adenine, ADP and Mn2+.
  Acta Crystallogr D Biol Crystallogr, 66, 145-154.
PDB codes: 3a7f 3a7g 3a7h 3a7i 3a7j
20637424 Y.W.Ng, D.Raghunathan, P.M.Chan, Y.Baskaran, D.J.Smith, C.H.Lee, C.Verma, and E.Manser (2010).
Why an A-loop phospho-mimetic fails to activate PAK1: understanding an inaccessible kinase state by molecular dynamics simulations.
  Structure, 18, 879-890.  
19350548 A.Kumar, P.R.Molli, S.B.Pakala, T.M.Bui Nguyen, S.K.Rayala, and R.Kumar (2009).
PAK thread from amoeba to mammals.
  J Cell Biochem, 107, 579-585.  
19160016 J.Eswaran, M.Soundararajan, and S.Knapp (2009).
Targeting group II PAKs in cancer and metastasis.
  Cancer Metastasis Rev, 28, 209-217.  
19237746 L.K.McNamara, D.M.Watterson, and J.S.Brunzelle (2009).
Structural insight into nucleotide recognition by human death-associated protein kinase.
  Acta Crystallogr D Biol Crystallogr, 65, 241-248.
PDB codes: 3eh9 3eha 3f5g 3f5u
19226137 R.Anand, J.Maksimoska, N.Pagano, E.Y.Wong, P.A.Gimotty, S.L.Diamond, E.Meggers, and R.Marmorstein (2009).
Toward the development of a potent and selective organoruthenium mammalian sterile 20 kinase inhibitor.
  J Med Chem, 52, 1602-1611.  
18239682 A.C.Pike, P.Rellos, F.H.Niesen, A.Turnbull, A.W.Oliver, S.A.Parker, B.E.Turk, L.H.Pearl, and S.Knapp (2008).
Activation segment dimerization: a mechanism for kinase autophosphorylation of non-consensus sites.
  EMBO J, 27, 704-714.
PDB codes: 2j51 2j7t 2j90 2jfl 2jfm 2uv2
18831043 F.Villa, M.Deak, D.R.Alessi, and D.M.van Aalten (2008).
Structure of the OSR1 kinase, a hypertension drug target.
  Proteins, 73, 1082-1087.
PDB code: 2vwi
18639460 J.Eswaran, M.Soundararajan, R.Kumar, and S.Knapp (2008).
UnPAKing the class differences among p21-activated kinases.
  Trends Biochem Sci, 33, 394-403.  
18282486 J.Weigelt, L.D.McBroom-Cerajewski, M.Schapira, Y.Zhao, C.H.Arrowsmith, and C.H.Arrowmsmith (2008).
Structural genomics and drug discovery: all in the family.
  Curr Opin Chem Biol, 12, 32-39.  
18644955 K.K.Ojo, J.R.Gillespie, A.J.Riechers, A.J.Napuli, C.L.Verlinde, F.S.Buckner, M.H.Gelb, M.M.Domostoj, S.J.Wells, A.Scheer, T.N.Wells, and W.C.Van Voorhis (2008).
Glycogen synthase kinase 3 is a potential drug target for African trypanosomiasis therapy.
  Antimicrob Agents Chemother, 52, 3710-3717.  
17937911 G.Bunkoczi, E.Salah, P.Filippakopoulos, O.Fedorov, S.Müller, F.Sobott, S.A.Parker, H.Zhang, W.Min, B.E.Turk, and S.Knapp (2007).
Structural and functional characterization of the human protein kinase ASK1.
  Structure, 15, 1215-1226.
PDB code: 2clq
17932789 O.Gileadi, S.Knapp, W.H.Lee, B.D.Marsden, S.Müller, F.H.Niesen, K.L.Kavanagh, L.J.Ball, F.von Delft, D.A.Doyle, U.C.Oppermann, and M.Sundström (2007).
The scientific impact of the Structural Genomics Consortium: a protein family and ligand-centered approach to medically-relevant human proteins.
  J Struct Funct Genomics, 8, 107-119.  
17392278 U.E.Rennefahrt, S.W.Deacon, S.A.Parker, K.Devarajan, A.Beeser, J.Chernoff, S.Knapp, B.E.Turk, and J.R.Peterson (2007).
Specificity profiling of Pak kinases allows identification of novel phosphorylation sites.
  J Biol Chem, 282, 15667-15678.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.