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PDBsum entry 2w9z

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protein Protein-protein interface(s) links
Transferase PDB id
2w9z
Jmol
Contents
Protein chains
246 a.a. *
287 a.a. *
Waters ×222
* Residue conservation analysis
PDB id:
2w9z
Name: Transferase
Title: Crystal structure of cdk4 in complex with a d-type cyclin
Structure: G1/s-specific cyclin-d1. Chain: a. Fragment: residues 16-271. Synonym: prad1 oncogene, bcl-1 oncogene, d-type cyclin. Engineered: yes. Cell division protein kinase 4. Chain: b. Synonym: cyclin-dependent kinase 4, psk-j3, cdk4. Engineered: yes.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf21.
Resolution:
2.45Å     R-factor:   0.228     R-free:   0.272
Authors: P.J.Day,A.Cleasby,I.J.Tickle,M.O.Reilly,J.E.Coyle, F.P.Holding,R.L.Mcmenamin,J.Yon,R.Chopra,C.Lengauer, H.Jhoti
Key ref:
P.J.Day et al. (2009). Crystal structure of human CDK4 in complex with a D-type cyclin. Proc Natl Acad Sci U S A, 106, 4166-4170. PubMed id: 19237565 DOI: 10.1073/pnas.0809645106
Date:
30-Jan-09     Release date:   10-Mar-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
No UniProt id for this chain
Struc: 246 a.a.
Protein chain
Pfam   ArchSchema ?
P11802  (CDK4_HUMAN) -  Cyclin-dependent kinase 4
Seq:
Struc:
303 a.a.
287 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chain B: E.C.2.7.11.22  - Cyclin-dependent kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
= ADP
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     cell cycle   4 terms 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     5 terms  

 

 
    reference    
 
 
DOI no: 10.1073/pnas.0809645106 Proc Natl Acad Sci U S A 106:4166-4170 (2009)
PubMed id: 19237565  
 
 
Crystal structure of human CDK4 in complex with a D-type cyclin.
P.J.Day, A.Cleasby, I.J.Tickle, M.O'Reilly, J.E.Coyle, F.P.Holding, R.L.McMenamin, J.Yon, R.Chopra, C.Lengauer, H.Jhoti.
 
  ABSTRACT  
 
The cyclin D1-cyclin-dependent kinase 4 (CDK4) complex is a key regulator of the transition through the G(1) phase of the cell cycle. Among the cyclin/CDKs, CDK4 and cyclin D1 are the most frequently activated by somatic genetic alterations in multiple tumor types. Thus, aberrant regulation of the CDK4/cyclin D1 pathway plays an essential role in oncogenesis; hence, CDK4 is a genetically validated therapeutic target. Although X-ray crystallographic structures have been determined for various CDK/cyclin complexes, CDK4/cyclin D1 has remained highly refractory to structure determination. Here, we report the crystal structure of CDK4 in complex with cyclin D1 at a resolution of 2.3 A. Although CDK4 is bound to cyclin D1 and has a phosphorylated T-loop, CDK4 is in an inactive conformation and the conformation of the heterodimer diverges from the previously known CDK/cyclin binary complexes, which suggests a unique mechanism for the process of CDK4 regulation and activation.
 
  Selected figure(s)  
 
Figure 1.
Ribbon diagram of the CDK4 (cyan)/cyclin D1 (orange) heterodimer. (A) The N- and C-terminal lobes of the kinase are labeled as are key secondary structural elements. (B) CDK7 (yellow) (Protein Data Bank ID code 1UA2) and CDK4 (cyan) (rmsd 1.053 Å). Both the αC-helix and T-loop of CDK7 adopt inactive conformations that are similar to the conformations of the equivalent secondary structural elements observed in CDK4.
Figure 3.
Architecture of the engineered loop preceding the αC-helix in the CDK4 (cyan)/cyclin D1 (orange) structure. (A) Akin to CDK2 and CDK6 (see Fig. S4) the apex of the loop is stabilized by hydrogen bonds from the loop main chain to a highly-conserved lysine (Lys[D1]112) and glutamate (Glu[D1]141) on the cyclin. The second glutamate (Glu[K4]44′) from the GE′E′G insertion mimics the interactions formed by the glutamate in the CDK6 structure. The loop is further stabilized by intramolecular H-bonds, which are not observed in either the CDK2 or CDK6 structures. A cyclin D1 Lys[D1]112–Glu mutation results in aberrant CDK4/cyclin D1 complex assembly and activation. (B) Residues in the vicinity of cyclin D1 (orange) Lys[D1]114. The Lys[D1]114–Glu mutation results in defective CDK4/cyclin D1 complex formation. Lys[D1]114 sits within an acidic environment formed by Glu[D1]74, Glu[D1]75, Glu[D1]76, Asp[D1]159, and Glu[D1]162. It would be anticipated that introduction of an additional negative charge into this environment would be highly destabilizing and significantly perturb correct CDK/cyclin association.
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21734724 E.A.Musgrove, C.E.Caldon, J.Barraclough, A.Stone, and R.L.Sutherland (2011).
Cyclin D as a therapeutic target in cancer.
  Nat Rev Cancer, 11, 558-572.  
  21306487 M.Ruiz-Miró, N.Colomina, R.M.Fernández, E.Garí, C.Gallego, and M.Aldea (2011).
Translokin (Cep57) interacts with cyclin D1 and prevents its nuclear accumulation in quiescent fibroblasts.
  Traffic, 12, 549-562.  
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.  
21253554 R.Conyers, S.Young, and D.M.Thomas (2011).
Liposarcoma: molecular genetics and therapeutics.
  Sarcoma, 2011, 483154.  
21242975 R.M.Fernández, M.Ruiz-Miró, X.Dolcet, M.Aldea, and E.Garí (2011).
Cyclin D1 interacts and collaborates with Ral GTPases enhancing cell detachment and motility.
  Oncogene, 30, 1936-1946.  
21358637 Y.Wang, J.C.Fisher, R.Mathew, L.Ou, S.Otieno, J.Sublet, L.Xiao, J.Chen, M.F.Roussel, and R.W.Kriwacki (2011).
Intrinsic disorder mediates the diverse regulatory functions of the Cdk inhibitor p21.
  Nat Chem Biol, 7, 214-221.  
  20139727 K.A.Merrick, and R.P.Fisher (2010).
Putting one step before the other: distinct activation pathways for Cdk1 and Cdk2 bring order to the mammalian cell cycle.
  Cell Cycle, 9, 706-714.  
  20560705 P.Sarita Rajender, D.Ramasree, K.Bhargavi, M.Vasavi, and V.Uma (2010).
Selective inhibition of proteins regulating CDK/cyclin complexes: strategy against cancer--a review.
  J Recept Signal Transduct Res, 30, 206-213.  
19391195 F.Cesari (2009).
Change of guard at the checkpoint.
  Nat Rev Mol Cell Biol, 10, 305.  
19487459 L.Bockstaele, X.Bisteau, S.Paternot, and P.P.Roger (2009).
Differential regulation of cyclin-dependent kinase 4 (CDK4) and CDK6, evidence that CDK4 might not be activated by CDK7, and design of a CDK6 activating mutation.
  Mol Cell Biol, 29, 4188-4200.  
19888216 Q.Zhong, N.Simonis, Q.R.Li, B.Charloteaux, F.Heuze, N.Klitgord, S.Tam, H.Yu, K.Venkatesan, D.Mou, V.Swearingen, M.A.Yildirim, H.Yan, A.Dricot, D.Szeto, C.Lin, T.Hao, C.Fan, S.Milstein, D.Dupuy, R.Brasseur, D.E.Hill, M.E.Cusick, and M.Vidal (2009).
Edgetic perturbation models of human inherited disorders.
  Mol Syst Biol, 5, 321.  
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.