spacer
spacer
Go to PDB code: 
protein Protein-protein interface(s) links
Antitumor protein PDB-id
1gh6
Biological unit* = asymmetric unit, as shown
(*as deduced by PQS)
Main view
    Jmol     Help!  
Contents
Description
Header details
Header records
References
PROCHECK
Protein chains
114 a.a. *
326 a.a. *

* Residue conservation analysis
Tools
Image Generation
AstexViewer™@PDBe
Run PROCHECK
Clefts Calculation
  
Right view Bottom view
PDB id: 1gh6
Name: Antitumor protein
Title: Retinoblastoma pocket complexed with sv40 large t antigen

Structure:
Large t antigen. Chain: a. Engineered: yes. Retinoblastoma-associated protein. Chain: b

Source:
Simian virus 40. Organism_taxid: 10633. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693. Homo sapiens. Human. Organism_taxid: 9606

Biological unit:
Dimer (from PQS)

UniProt:
Chain A: P03070 (LT_SV40)
Pfam   ArchSchema ?
Seq:
Struc:
Seq:
Struc:
Seq: 708 a.a.
Struc: 114 a.a.*

Chain B: P06400 (RB_HUMAN)
Pfam   ArchSchema ?
Seq:
Struc:
Seq:
Struc:
Seq:
Struc:
Seq: 928 a.a.
Struc: 326 a.a.*
Key:    PfamA domain
 Secondary structure  CATH domain
* PDB and UniProt seqs differ at 7 residue positions (black crosses)

Resolution:
3.20Å

R-factor:
0.248

R-free:
0.314

Authors:
H.Y.Kim,Y.Cho

Key ref:
H.Y.Kim et al. (2001). Structural basis for the inactivation of retinoblastoma tumor suppressor by SV40 large T antigen.. EMBO J, 20, 295-304. [PubMed id: 11226179] [DOI: 10.1093/emboj/20.1.295]

Date:
15-Nov-00

Release date:
15-Nov-01
Quick_links
RCSB
PDBe
SRS
MMDB
JenaLib
OCA
PDBWiki
Proteopedia
CATH
SCOP
FSSP
HSSP
PDBSWS
PQS
ProSAT
Whatcheck
Procheck
Go to PROCHECK summary
Clefts
Clefts
Surface
RasMol surface
spacer
spacer

 
    Key reference    
 
 
DOI no: 10.1093/emboj/20.1.295 EMBO J 20:295-304 (2001)
PubMed id: 11226179  
 
 
Structural basis for the inactivation of retinoblastoma tumor suppressor by SV40 large T antigen.
H.Y.Kim, B.Y.Ahn, Y.Cho.
 
  ABSTRACT  
 
Inactivation of the retinoblastoma (Rb) tumor suppressor by Simian virus 40 (SV40) large T antigen is one of the central features of tumorigenesis induced by SV40. Both the N-terminal J domain and the LxCxE motif of large T antigen are required for inactivation of Rb. The crystal structure of the N-terminal region (residues 7-117) of SV40 large T antigen bound to the pocket domain of Rb reveals that large T antigen contains a four-helix bundle, and residues from helices alpha2 and alpha4 and from a loop containing the LxCxE motif participate in the interactions with Rb. The two central helices and a connecting loop in large T antigen have structural similarities with the J domains of the molecular chaperones DnaJ and HDJ-1, suggesting that large T antigen may use a chaperone mechanism for its biological function. However, there are significant differences between large T antigen and the molecular chaperones in other regions and these differences are likely to provide the specificity needed for large T antigen to inactivate Rb.
 
  Selected figure(s)  
 
Figure 2.
Figure 2 (A) Overall structure of the N-terminal portion of SV40 large T antigen (residues 7 -117). The two central helices and connecting loop are colored red, surrounding helices are in green and the other loops are colored gray. (B) Sequence alignment of T antigen with other J domain-containing proteins. The conserved residues are boxed with yellow and green. Residues participating in core formation (side chains with <20% of accessible surface area) are indicated by red circles and those interacting with Rb by blue triangles. JCV, large T antigen of JC virus; BKV, large T antigen of BK virus; PyV, large T antigen of murine polyoma virus. The conserved residues in HPV E7 and adenovirus E1 are boxed in red lines. (C) Structural comparison of SV40 large T antigen (yellow) with the J domain of DnaJ (blue) and HDJ-1 (red). Helix 4' is from DnaJ or HDJ-1, and helix 4 is from large T antigen. (D) Stereo view of the hydrophobic core structure of large T antigen. Helix 1 is colored green, 2 and 3 magenta, and 4 light blue. (E) The local structure of the L2 loop of large T antigen. The side chain of Phe41 is stacked between Trp91 (green) in helix 4 and Pro43.
Figure 5.
Figure 5 (A) Schematic representation of the dissociation mechanism of the Rb -E2F complex by large T antigen and hsc70. The model is based on the DnaJ -DnaK chaperone mechanism proposed by Laufen et al. (1999); see text. (B) Surface representation of a model for the interaction between the Rb pocket domain -large T antigen complex and hsc70 (DnaK). Residues Arg167, Asn170 and Thr173 are critical for the interaction with the J domain, whereas Asn147, Asp148 and Glu152 do not a play significant role in binding to the J domain (Suh et al., 1998). The model is based on information from NMR perturbation and mutational analysis of the DnaJ -DnaK interaction (see text). The solvent-accessible surface was calculated using GRASP (Nicholls et al., 1991) with a water probe radius of 1.4 Å, and is colored by electrostatic potential of large T antigen and hsc70 in the range less than -10 to >10 K[b]T, where K[b] is the Boltzman constant and T is the temperature. The positive potential is shown in blue and negative in red.
 
  The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO J (2001, 20, 295-304) copyright 2001.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20088881 L.B.Chemes, I.E.Sánchez, C.Smal, and G.de Prat-Gay (2010).
Targeting mechanism of the retinoblastoma tumor suppressor by a prototypical viral oncoprotein. Structural modularity, intrinsic disorder and phosphorylation of human papillomavirus E7.
  FEBS J, 277, 973-988.  
19146698 A.J.Hume, and R.F.Kalejta (2009).
Regulation of the retinoblastoma proteins by the human herpesviruses.
  Cell Div, 4, 1.  
19712106 A.Stein, R.A.Pache, P.Bernadó, M.Pons, and P.Aloy (2009).
Dynamic interactions of proteins in complex networks: a more structured view.
  FEBS J, 276, 5390-5405.  
19598264 K.Dantur, L.Alonso, E.Castaño, L.Morelli, J.M.Centeno-Crowley, S.Vighi, and G.de Prat-Gay (2009).
Cytosolic accumulation of HPV16 E7 oligomers supports different transformation routes for the prototypic viral oncoprotein: the amyloid-cancer connection.
  Int J Cancer, 125, 1902-1911.  
19144705 W.Wang, and D.T.Simmons (2009).
Simian virus 40 large T antigen can specifically unwind the central palindrome at the origin of DNA replication.
  J Virol, 83, 3312-3322.  
18579587 A.Kumar, W.S.Joo, G.Meinke, S.Moine, E.N.Naumova, and P.A.Bullock (2008).
Evidence for a structural relationship between BRCT domains and the helicase domains of the replication initiators encoded by the Polyomaviridae and Papillomaviridae families of DNA tumor viruses.
  J Virol, 82, 8849-8862.  
18596940 A.Stein, and P.Aloy (2008).
Contextual specificity in peptide-mediated protein interactions.
  PLoS ONE, 3, e2524.  
18353955 X.Zhao, R.J.Madden-Fuentes, B.X.Lou, J.M.Pipas, J.Gerhardt, C.J.Rigell, and E.Fanning (2008).
Ataxia telangiectasia-mutated damage-signaling kinase- and proteasome-dependent destruction of Mre11-Rad50-Nbs1 subunits in Simian virus 40-infected primate cells.
  J Virol, 82, 5316-5328.  
17287270 A.Kumar, G.Meinke, D.K.Reese, S.Moine, P.J.Phelan, A.Fradet-Turcotte, J.Archambault, A.Bohm, and P.A.Bullock (2007).
Model for T-antigen-dependent melting of the simian virus 40 core origin based on studies of the interaction of the beta-hairpin with DNA.
  J Virol, 81, 4808-4818.  
17237519 C.M.Wright, S.W.Fewell, M.L.Sullivan, J.M.Pipas, S.C.Watkins, and J.L.Brodsky (2007).
The Hsp40 molecular chaperone Ydj1p, along with the protein kinase C pathway, affects cell-wall integrity in the yeast Saccharomyces cerevisiae.
  Genetics, 175, 1649-1664.  
17854503 F.A.Dick (2007).
Structure-function analysis of the retinoblastoma tumor suppressor protein - is the whole a sum of its parts?
  Cell Div, 2, 26.  
17253903 G.Meinke, P.Phelan, S.Moine, E.Bochkareva, A.Bochkarev, P.A.Bullock, and A.Bohm (2007).
The crystal structure of the SV40 T-antigen origin binding domain in complex with DNA.
  PLoS Biol, 5, e23.
PDB codes: 2if9 2ntc
17608567 U.S.Cho, S.Morrone, A.A.Sablina, J.D.Arroyo, W.C.Hahn, and W.Xu (2007).
Structural basis of PP2A inhibition by small t antigen.
  PLoS Biol, 5, e202.  
17301125 W.Wang, D.Manna, and D.T.Simmons (2007).
Role of the hydrophilic channels of simian virus 40 T-antigen helicase in DNA replication.
  J Virol, 81, 4510-4519.  
17974914 X.Liu, and R.Marmorstein (2007).
Structure of the retinoblastoma protein bound to adenovirus E1A reveals the molecular basis for viral oncoprotein inactivation of a tumor suppressor.
  Genes Dev, 21, 2711-2716.
PDB code: 2r7g
17529992 Y.Chen, Y.Xu, Q.Bao, Y.Xing, Z.Li, Z.Lin, J.B.Stock, P.D.Jeffrey, and Y.Shi (2007).
Structural and biochemical insights into the regulation of protein phosphatase 2A by small t antigen of SV40.
  Nat Struct Mol Biol, 14, 527-534.
PDB code: 2pkg
16936748 A.Felsani, A.M.Mileo, and M.G.Paggi (2006).
Retinoblastoma family proteins as key targets of the small DNA virus oncoproteins.
  Oncogene, 25, 5277-5285.  
17005644 D.K.Reese, G.Meinke, A.Kumar, S.Moine, K.Chen, J.L.Sudmeier, W.Bachovchin, A.Bohm, and P.A.Bullock (2006).
Analyses of the interaction between the origin binding domain from simian virus 40 T antigen and single-stranded DNA provide insights into DNA unwinding and initiation of DNA replication.
  J Virol, 80, 12248-12259.  
17139255 E.Bochkareva, D.Martynowski, A.Seitova, and A.Bochkarev (2006).
Structure of the origin-binding domain of simian virus 40 large T antigen bound to DNA.
  EMBO J, 25, 5961-5969.
PDB codes: 2ipr 2itj 2itl 2nl8
16611889 G.Meinke, P.A.Bullock, and A.Bohm (2006).
Crystal structure of the simian virus 40 large T-antigen origin-binding domain.
  J Virol, 80, 4304-4312.
PDB code: 2fuf
17109635 H.X.Guo, W.Cun, L.D.Liu, S.Z.Dong, L.C.Wang, C.H.Dong, and Q.H.Li (2006).
Protein encoded by HSV-1 stimulation-related gene 1 (HSRG1) interacts with and inhibits SV40 large T antigen.
  Cell Prolif, 39, 507-518.  
16936749 M.K.White, and K.Khalili (2006).
Interaction of retinoblastoma protein family members with large T-antigen of primate polyomaviruses.
  Oncogene, 25, 5286-5293.  
16951253 W.Lilyestrom, M.G.Klein, R.Zhang, A.Joachimiak, and X.S.Chen (2006).
Crystal structure of SV40 large T-antigen bound to p53: interplay between a viral oncoprotein and a cellular tumor suppressor.
  Genes Dev, 20, 2373-2382.
PDB code: 2h1l
15806172 A.Ledl, D.Schmidt, and S.Müller (2005).
Viral oncoproteins E1A and E7 and cellular LxCxE proteins repress SUMO modification of the retinoblastoma tumor suppressor.
  Oncogene, 24, 3810-3818.  
16299533 D.Ahuja, M.T.Sáenz-Robles, and J.M.Pipas (2005).
SV40 large T antigen targets multiple cellular pathways to elicit cellular transformation.
  Oncogene, 24, 7729-7745.  
16047383 E.Dees, J.B.Robertson, M.Ashe, L.M.Pabón-Peña, D.Bader, and R.L.Goodwin (2005).
LEK1 protein expression in normal and dysregulated cardiomyocyte mitosis.
  Anat Rec A Discov Mol Cell Evol Biol, 286, 823-832.  
15987899 F.Hennessy, W.S.Nicoll, R.Zimmermann, M.E.Cheetham, and G.L.Blatch (2005).
Not all J domains are created equal: implications for the specificity of Hsp40-Hsp70 interactions.
  Protein Sci, 14, 1697-1709.  
16140746 J.S.Kasper, H.Kuwabara, T.Arai, S.H.Ali, and J.A.DeCaprio (2005).
Simian virus 40 large T antigen's association with the CUL7 SCF complex contributes to cellular transformation.
  J Virol, 79, 11685-11692.  
16014958 K.A.Whalen, R.de Jesus, J.A.Kean, and B.S.Schaffhausen (2005).
Genetic analysis of the polyomavirus DnaJ domain.
  J Virol, 79, 9982-9990.  
16118215 M.Singh, M.Krajewski, A.Mikolajka, and T.A.Holak (2005).
Molecular determinants for the complex formation between the retinoblastoma protein and LXCXE sequences.
  J Biol Chem, 280, 37868-37876.  
  15629761 W.J.Freed, P.Zhang, J.F.Sanchez, O.Dillon-Carter, M.Coggiano, S.L.Errico, B.D.Lewis, and M.E.Truckenmiller (2005).
Truncated N-terminal mutants of SV40 large T antigen as minimal immortalizing agents for CNS cells.
  Exp Neurol, 191, S45-S59.  
14997555 B.A.Manjasetty, C.Quedenau, V.Sievert, K.Büssow, F.Niesen, H.Delbrück, and U.Heinemann (2004).
X-ray structure of human gankyrin, the product of a gene linked to hepatocellular carcinoma.
  Proteins, 55, 214-217.
PDB code: 1qym
15247252 D.Gai, D.Li, C.V.Finkielstein, R.D.Ott, P.Taneja, E.Fanning, and X.S.Chen (2004).
Insights into the oligomeric states, conformational changes, and helicase activities of SV40 large tumor antigen.
  J Biol Chem, 279, 38952-38959.  
14990710 D.K.Reese, K.R.Sreekumar, and P.A.Bullock (2004).
Interactions required for binding of simian virus 40 T antigen to the viral origin and molecular modeling of initial assembly events.
  J Virol, 78, 2921-2934.  
15078963 G.Arguello-Astorga, L.Lopez-Ochoa, L.J.Kong, B.M.Orozco, S.B.Settlage, and L.Hanley-Bowdoin (2004).
A novel motif in geminivirus replication proteins interacts with the plant retinoblastoma-related protein.
  J Virol, 78, 4817-4826.  
15273304 J.M.Gruschus, L.E.Greene, E.Eisenberg, and J.A.Ferretti (2004).
Experimentally biased model structure of the Hsc70/auxilin complex: substrate transfer and interdomain structural change.
  Protein Sci, 13, 2029-2044.  
15247253 K.Weisshart, S.Friedl, P.Taneja, H.P.Nasheuer, B.Schlott, F.Grosse, and E.Fanning (2004).
Partial proteolysis of simian virus 40 T antigen reveals intramolecular contacts between domains and conformation changes upon hexamer assembly.
  J Biol Chem, 279, 38943-38951.  
15084581 M.J.Dubin, P.H.Stokes, E.Y.Sum, R.S.Williams, V.A.Valova, P.J.Robinson, G.J.Lindeman, J.N.Glover, J.E.Visvader, and J.M.Matthews (2004).
Dimerization of CtIP, a BRCA1- and CtBP-interacting protein, is mediated by an N-terminal coiled-coil motif.
  J Biol Chem, 279, 26932-26938.  
14583607 Y.W.Chen, M.D.Allen, D.B.Veprintsev, J.Löwe, and M.Bycroft (2004).
The structure of the AXH domain of spinocerebellar ataxin-1.
  J Biol Chem, 279, 3758-3765.
PDB code: 1oa8
12598654 B.Xiao, J.Spencer, A.Clements, N.Ali-Khan, S.Mittnacht, C.Broceño, M.Burghammer, A.Perrakis, R.Marmorstein, and S.J.Gamblin (2003).
Crystal structure of the retinoblastoma tumor suppressor protein bound to E2F and the molecular basis of its regulation.
  Proc Natl Acad Sci U S A, 100, 2363-2368.
PDB code: 1o9k
14502556 D.W.Goodrich (2003).
How the other half lives, the amino-terminal domain of the retinoblastoma tumor suppressor protein.
  J Cell Physiol, 197, 169-180.  
12606716 K.Munger (2003).
Clefts, grooves, and (small) pockets: the structure of the retinoblastoma tumor suppressor in complex with its cellular target E2F unveiled.
  Proc Natl Acad Sci U S A, 100, 2165-2167.  
14633980 M.G.Gomez-Lorenzo, M.Valle, J.Frank, C.Gruss, C.O.Sorzano, X.S.Chen, L.E.Donate, and J.M.Carazo (2003).
Large T antigen on the simian virus 40 origin of replication: a 3D snapshot prior to DNA replication.
  EMBO J, 22, 6205-6213.  
12970459 P.Genevaux, F.Lang, F.Schwager, J.V.Vartikar, K.Rundell, J.M.Pipas, C.Georgopoulos, and W.L.Kelley (2003).
Simian virus 40 T antigens and J domains: analysis of Hsp40 cochaperone functions in Escherichia coli.
  J Virol, 77, 10706-10713.  
12941889 R.Roy, P.Trowbridge, Z.Yang, J.J.Champoux, and D.T.Simmons (2003).
The cap region of topoisomerase I binds to sites near both ends of simian virus 40 T antigen.
  J Virol, 77, 9809-9816.  
12718534 S.J.Landry (2003).
Structure and energetics of an allele-specific genetic interaction between dnaJ and dnaK: correlation of nuclear magnetic resonance chemical shift perturbations in the J-domain of Hsp40/DnaJ with binding affinity for the ATPase domain of Hsp70/DnaK.
  Biochemistry, 42, 4926-4936.  
  12787470 Y.Kudinov, C.L.Wiseman, and A.I.Kharazi (2003).
Phorbol myristate acetate and Bryostatin 1 rescue IFN-gamma inducibility of MHC class II molecules in LS1034 colorectal carcinoma cell line.
  Cancer Cell Int, 3, 4.  
12502741 C.Lee, J.H.Chang, H.S.Lee, and Y.Cho (2002).
Structural basis for the recognition of the E2F transactivation domain by the retinoblastoma tumor suppressor.
  Genes Dev, 16, 3199-3212.
PDB code: 1n4m
11921304 C.Lee, and Y.Cho (2002).
Interactions of SV40 large T antigen and other viral proteins with retinoblastoma tumour suppressor.
  Rev Med Virol, 12, 81-92.  
12040123 C.S.Sullivan, and J.M.Pipas (2002).
T antigens of simian virus 40: molecular chaperones for viral replication and tumorigenesis.
  Microbiol Mol Biol Rev, 66, 179-202.  
12021356 F.A.Dick, and N.J.Dyson (2002).
Three regions of the pRB pocket domain affect its inactivation by human papillomavirus E7 proteins.
  J Virol, 76, 6224-6234.  
  12454054 P.Genevaux, F.Schwager, C.Georgopoulos, and W.L.Kelley (2002).
Scanning mutagenesis identifies amino acid residues essential for the in vivo activity of the Escherichia coli DnaJ (Hsp40) J-domain.
  Genetics, 162, 1045-1053.  
12215534 P.T.Reilly, J.Wysocka, and W.Herr (2002).
Inactivation of the retinoblastoma protein family can bypass the HCF-1 defect in tsBN67 cell proliferation and cytokinesis.
  Mol Cell Biol, 22, 6767-6778.  
11932427 S.W.Fewell, D.M.Markle, and J.L.Brodsky (2002).
The carboxy terminus of simian virus 40 large T antigen is required to disrupt the yeast cell cycle.
  J Virol, 76, 4621-4624.  
11854498 S.W.Fewell, J.M.Pipas, and J.L.Brodsky (2002).
Mutagenesis of a functional chimeric gene in yeast identifies mutations in the simian virus 40 large T antigen J domain.
  Proc Natl Acad Sci U S A, 99, 2002-2007.  
11839806 V.D.Brown, and B.L.Gallie (2002).
The B-domain lysine patch of pRB is required for binding to large T antigen and release of E2F by phosphorylation.
  Mol Cell Biol, 22, 1390-1401.  
11700281 S.W.Fewell, K.J.Travers, J.S.Weissman, and J.L.Brodsky (2001).
The action of molecular chaperones in the early secretory pathway.
  Annu Rev Genet, 35, 149-191.  
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.