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PDBsum entry 1ung

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protein ligands Protein-protein interface(s) links
Cell cycle PDB id
1ung
Jmol
Contents
Protein chains
288 a.a. *
269 a.a. *
150 a.a. *
Ligands
ALH ×2
Waters ×294
* Residue conservation analysis
PDB id:
1ung
Name: Cell cycle
Title: Structural mechanism for the inhibition of cdk5-p25 by roscovitine, aloisine and indirubin.
Structure: Cell division protein kinase 5. Chain: a, b. Synonym: tau protein kinase ii, tpkii catalytic, serine/thr protein kinase pssalre, cyclin-dependent kinase 5. Engineered: yes. Mutation: yes. Cyclin-dependent kinase 5 activator 1. Chain: d, e. Fragment: residues 100-307.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
Biol. unit: Dimer (from PDB file)
Resolution:
2.30Å     R-factor:   0.216     R-free:   0.225
Authors: M.Mapelli,C.Crovace,L.Massimiliano,A.Musacchio
Key ref: M.Mapelli et al. (2005). Mechanism of CDK5/p25 binding by CDK inhibitors. J Med Chem, 48, 671-679. PubMed id: 15689152 DOI: 10.1021/jm049323m
Date:
10-Sep-03     Release date:   10-Nov-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q00535  (CDK5_HUMAN) -  Cyclin-dependent kinase 5
Seq:
Struc:
292 a.a.
288 a.a.*
Protein chain
Pfam   ArchSchema ?
Q00535  (CDK5_HUMAN) -  Cyclin-dependent kinase 5
Seq:
Struc:
292 a.a.
269 a.a.*
Protein chains
Pfam   ArchSchema ?
Q15078  (CD5R1_HUMAN) -  Cyclin-dependent kinase 5 activator 1
Seq:
Struc:
307 a.a.
150 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chains A, B: E.C.2.7.11.1  - Non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
=
ADP
Bound ligand (Het Group name = ALH)
matches with 42.42% similarity
+ 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  

 

 
    reference    
 
 
DOI no: 10.1021/jm049323m J Med Chem 48:671-679 (2005)
PubMed id: 15689152  
 
 
Mechanism of CDK5/p25 binding by CDK inhibitors.
M.Mapelli, L.Massimiliano, C.Crovace, M.A.Seeliger, L.H.Tsai, L.Meijer, A.Musacchio.
 
  ABSTRACT  
 
The cyclin-dependent kinases (CDK) CDK1, CDK2, CDK4, and CDK6 are serine/threonine protein kinases targeted in cancer therapy due to their role in cell cycle progression. The postmitotic CDK5 is involved in biological pathways important for neuronal migration and differentiation. CDK5 represents an attractive pharmacological target as its deregulation is implicated in various neurodegenerative diseases such as Alzheimer's, Parkinson's, and Niemann-Pick type C diseases, ischemia, and amyotrophic lateral sclerosis. We have generated an improved crystal form of CDK5 in complex with p25, a segment of the p35 neuronal activator. The crystals were used to solve the structure of CDK5/p25 with (R)-roscovitine and aloisine at a resolution of 2.2 and 2.3 A, respectively. The structure of CDK5/p25/roscovitine provides a rationale for the preference of CDK5 for the R over the S stereoisomer. Furthermore, roscovitine stabilized an unusual collapsed conformation of the glycine-rich loop, an important site of CDK regulation, and we report an investigation of the effects of glycine-rich loop phosphorylation on roscovitine binding. The CDK5/p25 crystals represent a valuable new tool for the identification and optimization of selective CDK inhibitors.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21287607 J.M.Hayes, V.T.Skamnaki, G.Archontis, C.Lamprakis, J.Sarrou, N.Bischler, A.L.Skaltsounis, S.E.Zographos, and N.G.Oikonomakos (2011).
Kinetics, in silico docking, molecular dynamics, and MM-GBSA binding studies on prototype indirubins, KT5720, and staurosporine as phosphorylase kinase ATP-binding site inhibitors: The role of water molecules examined.
  Proteins, 79, 703-719.  
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.  
20559856 Q.Chen, W.Cui, Y.Cheng, F.Zhang, and M.Ji (2011).
Studying the mechanism that enables paullones to selectively inhibit glycogen synthase kinase 3 rather than cyclin-dependent kinase 5 by molecular dynamics simulations and free-energy calculations.
  J Mol Model, 17, 795-803.  
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.  
20169620 K.Ravichandran, A.Pal, and R.Ravichandran (2010).
Effect of indirubin-3-monoxime against lung cancer as evaluated by histological and transmission electron microscopic studies.
  Microsc Res Tech, 73, 1053-1058.  
  21394236 M.Madra, and S.L.Sturley (2010).
Niemann-Pick type C pathogenesis and treatment: from statins to sugars.
  Clin Lipidol, 5, 387-395.  
20937706 T.K.Pareek, E.Lam, X.Zheng, D.Askew, A.B.Kulkarni, M.R.Chance, A.Y.Huang, K.R.Cooke, and J.J.Letterio (2010).
Cyclin-dependent kinase 5 activity is required for T cell activation and induction of experimental autoimmune encephalomyelitis.
  J Exp Med, 207, 2507-2519.  
21145489 X.H.Lowman, M.A.McDonnell, A.Kosloske, O.A.Odumade, C.Jenness, C.B.Karim, R.Jemmerson, and A.Kelekar (2010).
The proapoptotic function of Noxa in human leukemia cells is regulated by the kinase Cdk5 and by glucose.
  Mol Cell, 40, 823-833.  
19553566 J.Du, N.Wei, T.Guan, H.Xu, J.An, K.A.Pritchard, and Y.Shi (2009).
Inhibition of CDKS by roscovitine suppressed LPS-induced *NO production through inhibiting NFkappaB activation and BH4 biosynthesis in macrophages.
  Am J Physiol Cell Physiol, 297, C742-C749.  
19190331 J.H.DeMoe, S.Santaguida, J.R.Daum, A.Musacchio, and G.J.Gorbsky (2009).
A high throughput, whole cell screen for small molecule inhibitors of the mitotic spindle checkpoint identifies OM137, a novel Aurora kinase inhibitor.
  Cancer Res, 69, 1509-1516.  
18480410 K.H.Sun, Y.de Pablo, F.Vincent, E.O.Johnson, A.K.Chavers, and K.Shah (2008).
Novel genetic tools reveal Cdk5's major role in golgi fragmentation in Alzheimer's disease.
  Mol Biol Cell, 19, 3052-3069.  
18816110 K.Vougogiannopoulou, Y.Ferandin, K.Bettayeb, V.Myrianthopoulos, O.Lozach, Y.Fan, C.H.Johnson, P.Magiatis, A.L.Skaltsounis, E.Mikros, and L.Meijer (2008).
Soluble 3',6-substituted indirubins with enhanced selectivity toward glycogen synthase kinase -3 alter circadian period.
  J Med Chem, 51, 6421-6431.  
16770643 B.Zhang, V.B.Tan, K.M.Lim, T.E.Tay, and S.Zhuang (2007).
Study of the inhibition of cyclin-dependent kinases with roscovitine and indirubin-3'-oxime from molecular dynamics simulations.
  J Mol Model, 13, 79-89.  
17225251 D.Guiffant, D.Tribouillard, F.Gug, H.Galons, L.Meijer, M.Blondel, and S.Bach (2007).
Identification of intracellular targets of small molecular weight chemical compounds using affinity chromatography.
  Biotechnol J, 2, 68-75.  
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.  
17619233 S.Timsit, and B.Menn (2007).
Cerebral ischemia, cell cycle elements and Cdk5.
  Biotechnol J, 2, 958-966.  
17194758 T.K.Pareek, J.Keller, S.Kesavapany, N.Agarwal, R.Kuner, H.C.Pant, M.J.Iadarola, R.O.Brady, and A.B.Kulkarni (2007).
Cyclin-dependent kinase 5 modulates nociceptive signaling through direct phosphorylation of transient receptor potential vanilloid 1.
  Proc Natl Acad Sci U S A, 104, 660-665.  
16702956 J.Ribas, K.Bettayeb, Y.Ferandin, M.Knockaert, X.Garrofé-Ochoa, F.Totzke, C.Schächtele, J.Mester, P.Polychronopoulos, P.Magiatis, A.L.Skaltsounis, J.Boix, and L.Meijer (2006).
7-Bromoindirubin-3'-oxime induces caspase-independent cell death.
  Oncogene, 25, 6304-6318.  
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.  
16274748 R.L.Neve, and D.L.McPhie (2006).
The cell cycle as a therapeutic target for Alzheimer's disease.
  Pharmacol Ther, 111, 99.  
15985434 L.Tang, M.H.Li, P.Cao, F.Wang, W.R.Chang, S.Bach, J.Reinhardt, Y.Ferandin, H.Galons, Y.Wan, N.Gray, L.Meijer, T.Jiang, and D.C.Liang (2005).
Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives.
  J Biol Chem, 280, 31220-31229.
PDB codes: 1ygj 1ygk 1yhj
15975926 S.Bach, M.Knockaert, J.Reinhardt, O.Lozach, S.Schmitt, B.Baratte, M.Koken, S.P.Coburn, L.Tang, T.Jiang, D.C.Liang, H.Galons, J.F.Dierick, L.A.Pinna, F.Meggio, F.Totzke, C.Schächtele, A.S.Lerman, A.Carnero, Y.Wan, N.Gray, and L.Meijer (2005).
Roscovitine targets, protein kinases and pyridoxal kinase.
  J Biol Chem, 280, 31208-31219.  
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.