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Structure of the retinoblastoma tumour-suppressor pocket domain bound to a peptide from HPV E7

Nature volume 391, pages 859–865 (1998)Cite this article

Abstract

The pocket domain of the retinoblastoma (Rb) tumour suppressor is central to Rb function, and is frequently inactivated by the binding of the human papilloma virus E7 oncoprotein in cervical cancer. The crystal structure of the Rb pocket bound to a nine-residue E7 peptide containing the LxCxE motif, shared by other Rb-binding viral and cellular proteins, shows that the LxCxE peptide binds a highly conserved groove on the B-box portion of the pocket; the A-box portion appears to be required for the stable folding of the B box. Also highly conserved is the extensive A–B interface, suggesting that it may be an additional protein-binding site. The A and B boxes each contain the cyclin-fold structural motif, with the LxCxE-binding site on the B-box cyclin fold being similar to a Cdk2-binding site of cyclin A and to a TBP-binding site of TFIIB.

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Figure 1: The A–B pocket is central to Rb function.
Figure 2: Conserved residues of the Rb pocket map to the LxCxE binding site or to the A–B interface, as well as to the hydrophobic cores of the A and B boxes.
Figure 3: The A–B interface is like a folded structural domain, and is highly conserved.
Figure 4: The E7 LxCxE binds as an extended peptide onto a conserved groove of the B box.
Figure 5: Rb, cyclin A and TFIIB use a common feature of their structurally conserved cyclin folds to bind their target proteins.

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Acknowledgements

We thank S. Geromanos and H. Erdjument-Bromage of the Sloan-Kettering Microchemistry Facility for N-terminal sequence and mass spectroscopic analyses; M. Ewen, T. D. Gilmore, W. Harper, M. H. Lee and J. Y. J.Wang for cDNA clones; and C. Ogata of the National Synchrotron Light Source X4A beam line and the staff of the Cornell High Energy Synchrotron Source MacChess for help with data collection. This work was supported by the NIH, the Howard Hughes Medical Institute, the Pew Charitable Trusts, the Arnold and Mabel Beckman Foundation, the Dewitt Wallace Foundation and the Samuel and May Rudin Foundation.

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  1. Cellular Biochemistry and Biophysics Program, New York, 10021, New York, USA

    Alicia A. Russo

  2. Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, 10021, New York, USA

    Jie-Oh Lee & Nikola P. Pavletich

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Correspondence to Nikola P. Pavletich.

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Lee, JO., Russo, A. & Pavletich, N. Structure of the retinoblastoma tumour-suppressor pocket domain bound to a peptide from HPV E7. Nature 391, 859–865 (1998). https://doi.org/10.1038/36038

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