PDBsum entry 1yhv

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protein links
Signaling protein, transferase PDB id
Protein chain
293 a.a. *
Waters ×218
* Residue conservation analysis
PDB id:
Name: Signaling protein, transferase
Title: Crystal structure of pak1 kinase domain with two point mutations (k299r, t423e)
Structure: Serine/threonine-protein kinase pak 1. Chain: a. Fragment: kinase domain. Synonym: p21-activated kinase 1. Pak-1. P65-pak. Alpha-pak. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pak1. Expressed in: escherichia coli. Expression_system_taxid: 562.
1.80Å     R-factor:   0.220     R-free:   0.240
Authors: M.Lei,M.A.Robinson,S.C.Harrison
Key ref:
M.Lei et al. (2005). The active conformation of the PAK1 kinase domain. Structure, 13, 769-778. PubMed id: 15893667 DOI: 10.1016/j.str.2005.03.007
10-Jan-05     Release date:   24-May-05    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q13153  (PAK1_HUMAN) -  Serine/threonine-protein kinase PAK 1
545 a.a.
293 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 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     transferase activity, transferring phosphorus-containing groups     4 terms  


DOI no: 10.1016/j.str.2005.03.007 Structure 13:769-778 (2005)
PubMed id: 15893667  
The active conformation of the PAK1 kinase domain.
M.Lei, M.A.Robinson, S.C.Harrison.
The p21-activated kinases (PAKs) participate in cytoskeletal control networks, downstream of Rho-family GTPases. A structure of PAK1 in an autoregulated, "off" state showed that a regulatory region, N-terminal to the kinase domain, forces the latter into an inactive conformation, prevents phosphorylation of Thr423 in the activation loop, and promotes dimerization. We have now determined structures at 1.8 A resolution for the free PAK1 kinase domain, with a mutation in the active site that blocks enzymatic activity, and for the same domain with a "phosphomimetic" mutation in the activation loop. The two very similar structures show that even in the absence of a phosphorylated Thr423, the kinase has an essentially active conformation. When Cdc42 binds the regulatory region and dissociates the dimer, PAK1 will be in an "intermediate-active" state, with a capacity to phosphorylate itself or other substrates even prior to modification of its activation loop.
  Selected figure(s)  
Figure 3.
Figure 3. The Activation Loop of PAK1 Compared with Those of Phosphorylase Kinase and Protein Kinase A in Their Active States
(A) PAK1 (from the double-mutant structure), with side chains that participate in an electrostatic network as described in the text.
(B) Phosphorylase kinase (PHK) (Lowe et al., 1997 [PDB accession code 2PHK]), which has a glutamate in the activation loop at the position corresponding to Thr423 of PAK1 (and mutated to Glu in our double mutant).
(C) Protein kinase A (PKA) (Narayana et al., 1997 [PDB accession code 1BKX]). The view in all three panels is as if looking from about 45 to the right in Figure 2A. Colors as in Figure 2.
  The above figure is reprinted by permission from Cell Press: Structure (2005, 13, 769-778) copyright 2005.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21474065 N.Jura, X.Zhang, N.F.Endres, M.A.Seeliger, T.Schindler, and J.Kuriyan (2011).
Catalytic control in the EGF receptor and its connection to general kinase regulatory mechanisms.
  Mol Cell, 42, 9.  
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
20209159 Y.H.Hsu, and J.A.Traugh (2010).
Reciprocally coupled residues crucial for protein kinase Pak2 activity calculated by statistical coupling analysis.
  PLoS One, 5, e9455.  
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.  
19160016 J.Eswaran, M.Soundararajan, and S.Knapp (2009).
Targeting group II PAKs in cancer and metastasis.
  Cancer Metastasis Rev, 28, 209-217.  
18761339 R.Bose, and X.Zhang (2009).
The ErbB kinase domain: structural perspectives into kinase activation and inhibition.
  Exp Cell Res, 315, 649-658.  
19120698 W.Wang, Y.Yang, Y.Gao, Q.Xu, F.Wang, S.Zhu, W.Old, K.Resing, N.Ahn, M.Lei, and X.Liu (2009).
Structural and mechanistic insights into Mps1 kinase activation.
  J Cell Mol Med, 13, 1679-1694.
PDB code: 3dbq
19306398 Y.Li, and A.G.Palmer (2009).
Domain swapping in the kinase superfamily: OSR1 joins the mix.
  Protein Sci, 18, 678-681.  
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.  
18931661 M.Higuchi, K.Onishi, C.Kikuchi, and Y.Gotoh (2008).
Scaffolding function of PAK in the PDK1-Akt pathway.
  Nat Cell Biol, 10, 1356-1364.  
18501020 N.F.Saunders, R.I.Brinkworth, T.Huber, B.E.Kemp, and B.Kobe (2008).
Predikin and PredikinDB: a computational framework for the prediction of protein kinase peptide specificity and an associated database of phosphorylation sites.
  BMC Bioinformatics, 9, 245.  
18775312 P.Filippakopoulos, M.Kofler, O.Hantschel, G.D.Gish, F.Grebien, E.Salah, P.Neudecker, L.E.Kay, B.E.Turk, G.Superti-Furga, T.Pawson, and S.Knapp (2008).
Structural coupling of SH2-kinase domains links Fes and Abl substrate recognition and kinase activation.
  Cell, 134, 793-803.
PDB codes: 3bkb 3cbl 3cd3
18984590 Y.H.Hsu, D.A.Johnson, and J.A.Traugh (2008).
Analysis of Conformational Changes during Activation of Protein Kinase Pak2 by Amide Hydrogen/Deuterium Exchange.
  J Biol Chem, 283, 36397-36405.  
18059449 D.J.Leahy (2007).
A monkey wrench in the kinase machine.
  Nat Struct Mol Biol, 14, 1120-1121.  
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
17292838 J.Eswaran, W.H.Lee, J.E.Debreczeni, P.Filippakopoulos, A.Turnbull, O.Fedorov, S.W.Deacon, J.R.Peterson, and S.Knapp (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.
PDB codes: 2bva 2c30 2cdz 2f57
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.  
18046415 X.Zhang, K.A.Pickin, R.Bose, N.Jura, P.A.Cole, and J.Kuriyan (2007).
Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface.
  Nature, 450, 741-744.
PDB codes: 2rf9 2rfd 2rfe
17079130 P.Pellicena, and J.Kuriyan (2006).
Protein-protein interactions in the allosteric regulation of protein kinases.
  Curr Opin Struct Biol, 16, 702-709.  
16014608 D.Matenia, B.Griesshaber, X.Y.Li, A.Thiessen, C.Johne, J.Jiao, E.Mandelkow, and E.M.Mandelkow (2005).
PAK5 kinase is an inhibitor of MARK/Par-1, which leads to stable microtubules and dynamic actin.
  Mol Biol Cell, 16, 4410-4422.  
16292343 M.Lammers, R.Rose, A.Scrima, and A.Wittinghofer (2005).
The regulation of mDia1 by autoinhibition and its release by Rho*GTP.
  EMBO J, 24, 4176-4187.
PDB code: 2bap
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 codes are shown on the right.