PDBsum entry: 1gh6

Antitumor protein

PDB id: 1gh6

Contents

Protein chains

114 a.a. *

326 a.a. *

* Residue conservation analysis

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

Biol. unit:

Dimer (from PQS)

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

Protein chain

P03070  (LT_SV40) -  Large T antigen

Seq: 708 a.a.

Struc: 114 a.a.*

Protein chain

P06400  (RB_HUMAN) -  Retinoblastoma-associated protein

Seq: 928 a.a.

Struc: 326 a.a.*

* PDB and UniProt seqs differ at 7 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 

• Biochemical function: heat shock protein binding (1 term)

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.