PDBsum entry 1h4l

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Kinase/kinase activator PDB id
Protein chains
278 a.a. *
147 a.a. *
Waters ×69
* Residue conservation analysis
PDB id:
Name: Kinase/kinase activator
Title: Structure and regulation of the cdk5-p25(nck5a) complex
Structure: Cell division protein kinase 5. Chain: a, b. Synonym: tau protein kinase ii catalytic subunit, cdk5. Engineered: yes. Cyclin-dependent kinase 5 activator. Chain: d, e. Fragment: residues 147-293. Synonym: cdk5 activator 1, cyclin-dependent kinase 5 regulatory subunit 1, tau protein kinase ii 23 kda
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9. Organism_taxid: 9606
Biol. unit: Dimer (from PDB file)
2.65Å     R-factor:   0.236     R-free:   0.287
Authors: C.Tarricone,R.Dhavan,J.Peng,L.B.Areces,L.-H.Tsai,A.Musacchio
Key ref:
C.Tarricone et al. (2001). Structure and regulation of the CDK5-p25(nck5a) complex. Mol Cell, 8, 657-669. PubMed id: 11583627 DOI: 10.1016/S1097-2765(01)00343-4
11-May-01     Release date:   14-Aug-02    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
Q00535  (CDK5_HUMAN) -  Cyclin-dependent kinase 5
292 a.a.
278 a.a.*
Protein chains
Pfam   ArchSchema ?
Q15078  (CD5R1_HUMAN) -  Cyclin-dependent kinase 5 activator 1
307 a.a.
147 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chains A, B: 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!
  Cellular component     synapse   20 terms 
  Biological process     protein localization to synapse   83 terms 
  Biochemical function     nucleotide binding     16 terms  


DOI no: 10.1016/S1097-2765(01)00343-4 Mol Cell 8:657-669 (2001)
PubMed id: 11583627  
Structure and regulation of the CDK5-p25(nck5a) complex.
C.Tarricone, R.Dhavan, J.Peng, L.B.Areces, L.H.Tsai, A.Musacchio.
CDK5 plays an indispensable role in the central nervous system, and its deregulation is involved in neurodegeneration. We report the crystal structure of a complex between CDK5 and p25, a fragment of the p35 activator. Despite its partial structural similarity with the cyclins, p25 displays an unprecedented mechanism for the regulation of a cyclin-dependent kinase. p25 tethers the unphosphorylated T loop of CDK5 in the active conformation. Residue Ser159, equivalent to Thr160 on CDK2, contributes to the specificity of the CDK5-p35 interaction. Its substitution with threonine prevents p35 binding, while the presence of alanine affects neither binding nor kinase activity. Finally, we provide evidence that the CDK5-p25 complex employs a distinct mechanism from the phospho-CDK2-cyclin A complex to establish substrate specificity.
  Selected figure(s)  
Figure 2.
Figure 2. Comparison of p25 and Cyclin A
Figure 6.
Figure 6. Role of Glu240 p25 in Substrate Recognition
  The above figures are reprinted by permission from Cell Press: Mol Cell (2001, 8, 657-669) copyright 2001.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21244636 N.Zhang, R.Zhong, H.Yan, and Y.Jiang (2011).
Structural features underlying selective inhibition of GSK3β by dibromocantharelline: implications for rational drug design.
  Chem Biol Drug Des, 77, 199-205.  
20013135 B.Zhang, Z.C.Su, T.E.Tay, and V.B.Tan (2010).
Mechanism of CDK5 activation revealed by steered molecular dynamics simulations and energy calculations.
  J Mol Model, 16, 1159-1168.  
20198710 J.C.Lozano, P.Schatt, V.Vergé, J.Gobinet, V.Villey, and G.Peaucellier (2010).
CDK5 is present in sea urchin and starfish eggs and embryos and can interact with p35, cyclin E and cyclin B3.
  Mol Reprod Dev, 77, 449-461.  
20392944 J.Zhang, H.Li, O.Yabut, H.Fitzpatrick, G.D'Arcangelo, and K.Herrup (2010).
Cdk5 suppresses the neuronal cell cycle by disrupting the E2F1-DP1 complex.
  J Neurosci, 30, 5219-5228.  
20336692 M.Rabiller, M.Getlik, S.Klüter, A.Richters, S.Tückmantel, J.R.Simard, and D.Rauh (2010).
Proteus in the world of proteins: conformational changes in protein kinases.
  Arch Pharm (Weinheim), 343, 193-206.  
21044075 S.Hisanaga, and R.Endo (2010).
Regulation and role of cyclin-dependent kinase activity in neuronal survival and death.
  J Neurochem, 115, 1309-1321.  
19263480 A.E.Kissler, N.Pettersson, A.Frölich, S.J.Sigrist, and B.Suter (2009).
Drosophila cdk5 is needed for locomotive behavior and NMJ elaboration, but seems dispensable for synaptic transmission.
  Dev Neurobiol, 69, 365-377.  
19457112 L.R.Orlando, R.Ayala, L.R.Kett, A.A.Curley, J.Duffner, D.C.Bragg, L.H.Tsai, A.W.Dunah, and A.B.Young (2009).
Phosphorylation of the homer-binding domain of group I metabotropic glutamate receptors by cyclin-dependent kinase 5.
  J Neurochem, 110, 557-569.  
19237555 T.Takaki, A.Echalier, N.R.Brown, T.Hunt, J.A.Endicott, and M.E.Noble (2009).
The structure of CDK4/cyclin D3 has implications for models of CDK activation.
  Proc Natl Acad Sci U S A, 106, 4171-4176.
PDB code: 3g33
18794371 S.Aviram, E.Simon, T.Gildor, F.Glaser, and D.Kornitzer (2008).
Autophosphorylation-induced degradation of the Pho85 cyclin Pcl5 is essential for response to amino acid limitation.
  Mol Cell Biol, 28, 6858-6869.  
18566585 S.Baumli, G.Lolli, E.D.Lowe, S.Troiani, L.Rusconi, A.N.Bullock, J.E.Debreczeni, S.Knapp, and L.N.Johnson (2008).
The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation.
  EMBO J, 27, 1907-1918.
PDB codes: 2ivx 3blh 3blq 3blr
17276406 D.R.Ledee, B.K.Tripathi, and P.S.Zelenka (2007).
The CDK5 activator, p39, binds specifically to myosin essential light chain.
  Biochem Biophys Res Commun, 354, 1034-1039.  
17373709 G.Lolli, and L.N.Johnson (2007).
Recognition of Cdk2 by Cdk7.
  Proteins, 67, 1048-1059.
PDB code: 2hic
17121855 H.Kamei, T.Saito, M.Ozawa, Y.Fujita, A.Asada, J.A.Bibb, T.C.Saido, H.Sorimachi, and S.Hisanaga (2007).
Suppression of calpain-dependent cleavage of the CDK5 activator p35 to p25 by site-specific phosphorylation.
  J Biol Chem, 282, 1687-1694.  
17145757 H.Lin, M.C.Chen, C.Y.Chiu, Y.M.Song, and S.Y.Lin (2007).
Cdk5 regulates STAT3 activation and cell proliferation in medullary thyroid carcinoma cells.
  J Biol Chem, 282, 2776-2784.  
16932754 H.Lin, T.Y.Lin, and J.L.Juang (2007).
Abl deregulates Cdk5 kinase activity and subcellular localization in Drosophila neurodegeneration.
  Cell Death Differ, 14, 607-615.  
18042456 K.Huang, I.Ferrin-O'Connell, W.Zhang, G.A.Leonard, E.K.O'Shea, and F.A.Quiocho (2007).
Structure of the Pho85-Pho80 CDK-cyclin complex of the phosphate-responsive signal transduction pathway.
  Mol Cell, 28, 614-623.
PDB codes: 2pk9 2pmi
17368005 L.Connell-Crowley, D.Vo, L.Luke, and E.Giniger (2007).
Drosophila lacking the Cdk5 activator, p35, display defective axon guidance, age-dependent behavioral deficits and reduced lifespan.
  Mech Dev, 124, 341-349.  
17353359 L.W.Tam, N.F.Wilson, and P.A.Lefebvre (2007).
A CDK-related kinase regulates the length and assembly of flagella in Chlamydomonas.
  J Cell Biol, 176, 819-829.  
17541419 M.P.Mazanetz, and P.M.Fischer (2007).
Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases.
  Nat Rev Drug Discov, 6, 464-479.  
17491008 Z.Hou, Q.Li, L.He, H.Y.Lim, X.Fu, N.S.Cheung, D.X.Qi, and R.Z.Qi (2007).
Microtubule association of the neuronal p35 activator of Cdk5.
  J Biol Chem, 282, 18666-18670.  
17095602 A.P.Kornev, N.M.Haste, S.S.Taylor, and L.F.Eyck (2006).
Surface comparison of active and inactive protein kinases identifies a conserved activation mechanism.
  Proc Natl Acad Sci U S A, 103, 17783-17788.  
16488127 A.R.Nebreda (2006).
CDK activation by non-cyclin proteins.
  Curr Opin Cell Biol, 18, 192-198.  
17054019 B.Zhang, V.B.Tan, K.M.Lim, and T.E.Tay (2006).
Molecular dynamics simulations on the inhibition of cyclin-dependent kinases 2 and 5 in the presence of activators.
  J Comput Aided Mol Des, 20, 395-404.  
16584130 J.Sridhar, N.Akula, and N.Pattabiraman (2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.
  AAPS J, 8, E204-E221.  
16407256 M.Otyepka, I.Bártová, Z.Kríz, and J.Koca (2006).
Different mechanisms of CDK5 and CDK2 activation as revealed by CDK5/p25 and CDK2/cyclin A dynamics.
  J Biol Chem, 281, 7271-7281.  
17060323 X.Fu, Y.K.Choi, D.Qu, Y.Yu, N.S.Cheung, and R.Z.Qi (2006).
Identification of nuclear import mechanisms for the neuronal Cdk5 activator.
  J Biol Chem, 281, 39014-39021.  
16191191 A.Cheng, S.Gerry, P.Kaldis, and M.J.Solomon (2005).
Biochemical characterization of Cdk2-Speedy/Ringo A2.
  BMC Biochem, 6, 19.  
15695825 C.P.Barrett, and M.E.Noble (2005).
Molecular motions of human cyclin-dependent kinase 2.
  J Biol Chem, 280, 13993-14005.  
15992363 Y.S.Zhu, T.Saito, A.Asada, S.Maekawa, and S.Hisanaga (2005).
Activation of latent cyclin-dependent kinase 5 (Cdk5)-p35 complexes by membrane dissociation.
  J Neurochem, 94, 1535-1545.  
15024385 E.R.Lacy, I.Filippov, W.S.Lewis, S.Otieno, L.Xiao, S.Weiss, L.Hengst, and R.W.Kriwacki (2004).
p27 binds cyclin-CDK complexes through a sequential mechanism involving binding-induced protein folding.
  Nat Struct Mol Biol, 11, 358-364.  
15350898 J.C.Cruz, and L.H.Tsai (2004).
Cdk5 deregulation in the pathogenesis of Alzheimer's disease.
  Trends Mol Med, 10, 452-458.  
15350897 P.D.Smith, M.J.O'Hare, and D.S.Park (2004).
CDKs: taking on a role as mediators of dopaminergic loss in Parkinson's disease.
  Trends Mol Med, 10, 445-451.  
15123286 Y.Wan, W.Hur, C.Y.Cho, Y.Liu, F.J.Adrian, O.Lozach, S.Bach, T.Mayer, D.Fabbro, L.Meijer, and N.S.Gray (2004).
Synthesis and target identification of hymenialdisine analogs.
  Chem Biol, 11, 247-259.  
12626523 D.Kamei, M.Murakami, Y.Nakatani, Y.Ishikawa, T.Ishii, and I.Kudo (2003).
Potential role of microsomal prostaglandin E synthase-1 in tumorigenesis.
  J Biol Chem, 278, 19396-19405.  
12688339 G.P.Studzinski, and J.S.Harrison (2003).
The neuronal cyclin-dependent kinase 5 activator p35Nck5a and Cdk5 activity in monocytic cells.
  Leuk Lymphoma, 44, 235-240.  
12769842 H.S.Yang, and P.W.Hinds (2003).
Increased ezrin expression and activation by CDK5 coincident with acquisition of the senescent phenotype.
  Mol Cell, 11, 1163-1176.  
14700633 L.Meijer, A.L.Skaltsounis, P.Magiatis, P.Polychronopoulos, M.Knockaert, M.Leost, X.P.Ryan, C.A.Vonica, A.Brivanlou, R.Dajani, C.Crovace, C.Tarricone, A.Musacchio, S.M.Roe, L.Pearl, and P.Greengard (2003).
GSK-3-selective inhibitors derived from Tyrian purple indirubins.
  Chem Biol, 10, 1255-1266.
PDB code: 1uv5
14700620 P.M.Fischer (2003).
CDK versus GSK-3 inhibition: a purple haze no longer?
  Chem Biol, 10, 1144-1146.  
11784720 H.Patzke, and L.H.Tsai (2002).
Calpain-mediated cleavage of the cyclin-dependent kinase-5 activator p39 to p29.
  J Biol Chem, 277, 8054-8060.  
12112670 J.Zhang, C.H.Luan, K.C.Chou, and G.V.Johnson (2002).
Identification of the N-terminal functional domains of Cdk5 by molecular truncation and computer modeling.
  Proteins, 48, 447-453.  
12230554 Y.L.Zheng, B.S.Li, N.D.Amin, W.Albers, and H.C.Pant (2002).
A peptide derived from cyclin-dependent kinase activator (p35) specifically inhibits Cdk5 activity and phosphorylation of tau protein in transfected cells.
  Eur J Biochem, 269, 4427-4434.  
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.